rs56201325

Variant names:

• chr2-178573201-T-C
• rs56201325
• NM_001267550.2:c.72931A>G

Your query was ambiguous. Multiple possible variants found:

• chr2-178573201-T-C
• chr2-178573201-T-G

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_001267550.2(TTN):​c.72931A>G​(p.Thr24311Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00425 in 1,608,610 control chromosomes in the GnomAD database, including 26 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0034 (3 hom., cov: 32)
  • Exomes 𝑓: 0.0043 (23 hom.)
• Consequence: TTN NM_001267550.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:21
• Conservation: PhyloP100: 1.20
• Publications: 14 publications found

Genes affected

TTN (HGNC:12403): (titin) This gene encodes a large abundant protein of striated muscle. The product of this gene is divided into two regions, a N-terminal I-band and a C-terminal A-band. The I-band, which is the elastic part of the molecule, contains two regions of tandem immunoglobulin domains on either side of a PEVK region that is rich in proline, glutamate, valine and lysine. The A-band, which is thought to act as a protein-ruler, contains a mixture of immunoglobulin and fibronectin repeats, and possesses kinase activity. An N-terminal Z-disc region and a C-terminal M-line region bind to the Z-line and M-line of the sarcomere, respectively, so that a single titin molecule spans half the length of a sarcomere. Titin also contains binding sites for muscle associated proteins so it serves as an adhesion template for the assembly of contractile machinery in muscle cells. It has also been identified as a structural protein for chromosomes. Alternative splicing of this gene results in multiple transcript variants. Considerable variability exists in the I-band, the M-line and the Z-disc regions of titin. Variability in the I-band region contributes to the differences in elasticity of different titin isoforms and, therefore, to the differences in elasticity of different muscle types. Mutations in this gene are associated with familial hypertrophic cardiomyopathy 9, and autoantibodies to titin are produced in patients with the autoimmune disease scleroderma. [provided by RefSeq, Feb 2012]

TTN-AS1 (HGNC:44124): (TTN antisense RNA 1) This gene encodes a non-coding RNA transcribed from the opposite strand to the titin gene. [provided by RefSeq, Aug 2016]

ACMG classification

Our verdict: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0057098866).
• BP6: Variant 2-178573201-T-C is Benign according to our data. Variant chr2-178573201-T-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 47318.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00344 (524/152232) while in subpopulation NFE AF = 0.00566 (385/67990). AF 95% confidence interval is 0.0052. There are 3 homozygotes in GnomAd4. There are 255 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 3 AD,AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001267550.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TTN	NM_001267550.2	MANE Select	c.72931A>G	p.Thr24311Ala	missense	Exon 326 of 363	NP_001254479.2
	TTN	NM_001256850.1		c.68008A>G	p.Thr22670Ala	missense	Exon 276 of 313	NP_001243779.1
	TTN	NM_133378.4		c.65227A>G	p.Thr21743Ala	missense	Exon 275 of 312	NP_596869.4

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TTN	ENST00000589042.5	TSL:5 MANE Select	c.72931A>G	p.Thr24311Ala	missense	Exon 326 of 363	ENSP00000467141.1
	TTN	ENST00000446966.2	TSL:1	c.72775A>G	p.Thr24259Ala	missense	Exon 324 of 361	ENSP00000408004.2
	TTN	ENST00000436599.2	TSL:1	c.72655A>G	p.Thr24219Ala	missense	Exon 324 of 361	ENSP00000405517.2

Frequencies

GnomAD3 genomes AF: 0.00344 AC: 524 AN: 152114 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.000772

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00144

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00734

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00566

Gnomad OTH AF: 0.00335

GnomAD2 exomes AF: 0.00399 AC: 975 AN: 244666 AF XY: 0.00394

Gnomad AFR exome AF: 0.000841

Gnomad AMR exome AF: 0.00114

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00890

Gnomad NFE exome AF: 0.00633

Gnomad OTH exome AF: 0.00492

GnomAD4 exome AF: 0.00433 AC: 6309 AN: 1456378 Hom.: 23 Cov.: 38 AF XY: 0.00422 AC XY: 3053 AN XY: 723912

African (AFR) AF: 0.000869 AC: 29 AN: 33382

American (AMR) AF: 0.00122 AC: 54 AN: 44428

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25858

East Asian (EAS) AF: 0.00 AC: 0 AN: 39566

South Asian (SAS) AF: 0.000129 AC: 11 AN: 85410

European-Finnish (FIN) AF: 0.00865 AC: 460 AN: 53186

Middle Eastern (MID) AF: 0.000523 AC: 3 AN: 5734

European-Non Finnish (NFE) AF: 0.00498 AC: 5521 AN: 1108680

Other (OTH) AF: 0.00384 AC: 231 AN: 60134

GnomAD4 genome AF: 0.00344 AC: 524 AN: 152232 Hom.: 3 Cov.: 32 AF XY: 0.00343 AC XY: 255 AN XY: 74416

African (AFR) AF: 0.000770 AC: 32 AN: 41564

American (AMR) AF: 0.00144 AC: 22 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5160

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.00734 AC: 78 AN: 10624

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00566 AC: 385 AN: 67990

Other (OTH) AF: 0.00331 AC: 7 AN: 2114

Alfa AF: 0.00485 Hom.: 6

Bravo AF: 0.00293

TwinsUK AF: 0.00512 AC: 19

ALSPAC AF: 0.00467 AC: 18

ESP6500AA AF: 0.000523 AC: 2

ESP6500EA AF: 0.00519 AC: 43

ExAC AF: 0.00466 AC: 563

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:21

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Benign:10

Nov 28, 2016

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Clinical Genetics, Academic Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Apr 09, 2025

Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Apr 01, 2021

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Jun 24, 2013

Biesecker Lab/Clinical Genomics Section, National Institutes of Health

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: research

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Jun 10, 2015

Eurofins Ntd Llc (ga)

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Mar 30, 2015

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

p.Thr21743Ala in exon 275 of TTN: This variant is not expected to have clinical significance because it has been identified in 0.9% (60/6610) of Finnish chromos omes and 0.7% (477/65890) European chromosomes, including two homozygous individ uals, by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs56201325).

Jul 06, 2020

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: TTN c.65227A>G (p.Thr21743Ala) results in a non-conservative amino acid change located in the A-band region (cardiodb.org) of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.004 in 244666 control chromosomes in the gnomAD database, including 3 homozygotes. The observed variant frequency is approximately 6.4- fold the estimated maximal expected allele frequency for a pathogenic variant in TTN causing Cardiomyopathy phenotype (0.00063), strongly suggesting that the variant is benign. c.65227A>G has been reported in the literature in individuals affected with Cardiomyopathy (examples- Lopes_2013, Pugh_2014, Campuzano_2015). These reports do not provide unequivocal conclusions about association of the variant with Cardiomyopathy. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. 13 clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments (benign, n=7; likely benign, n=4; uncertain significance, n=2). Based on the evidence outlined above, the variant was classified as likely benign.

not provided Benign:5

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Sep 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

TTN: BP4, BS2

Oct 17, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Feb 10, 2015

Genetic Services Laboratory, University of Chicago

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Autosomal recessive limb-girdle muscular dystrophy type 2J Uncertain:1

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.

Early-onset myopathy with fatal cardiomyopathy Uncertain:1

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.

Autosomal recessive limb-girdle muscular dystrophy type 2J;C1858763:Dilated cardiomyopathy 1G Benign:1

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Cardiomyopathy Benign:1

Jan 29, 2018

CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Dilated cardiomyopathy 1G Benign:1

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.

Myopathy, myofibrillar, 9, with early respiratory failure Benign:1

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign.

Tibial muscular dystrophy Benign:1

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign.

Cardiovascular phenotype Benign:1

Jul 29, 2020

Ambry Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

General population or subpopulation frequency is too high to be a pathogenic mutation based on disease/syndrome prevalence and penetrance

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.051
BayesDel_addAF	Benign	-0.51	T
BayesDel_noAF	Benign	-0.50
CADD	Benign	17
DANN	Benign	0.82
Eigen	Benign	-0.53
Eigen_PC	Benign	-0.33
FATHMM_MKL	Benign	0.68	D
LIST_S2	Benign	0.72	T
M_CAP	Benign	0.0078	T
MetaRNN	Benign	0.0057	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.63	N
PhyloP100		1.2
PrimateAI	Benign	0.38	T
PROVEAN	Uncertain	-2.6	D
REVEL	Benign	0.054
Sift	Benign	0.32	T
Polyphen		0.0	B
Vest4		0.11
MVP		0.072
MPC		0.082
ClinPred		0.0067	T
GERP RS		3.6
Mutation Taster		=99/1	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs56201325; hg19: chr2-179437928; COSMIC: COSV99045615; COSMIC: COSV99045615;