rs72677243

chr2-178614561-A-G

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 1P and 9B. PP2 BP4_Strong BP6 BS2

The NM_001267550.2(TTN):c.48953T>C(p.Ile16318Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00103 in 1,612,356 control chromosomes in the GnomAD database, including 8 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I16318L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00094 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0010 (8 hom.)
• Consequence: TTN NM_001267550.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:6 B:13
• Conservation: PhyloP100: 9.19

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

Verdict is Benign. Variant got -8 ACMG points.

• PP2: Missense variant where missense usually causes diseases, TTN
• BP4: Computational evidence support a benign effect (MetaRNN=0.008417815).
• BP6: Variant 2-178614561-A-G is Benign according to our data. Variant chr2-178614561-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 47025.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=5, Benign=8, Likely_benign=5}. Variant chr2-178614561-A-G is described in Lovd as [Likely_benign]. Variant chr2-178614561-A-G is described in Lovd as [Benign].
• BS2: High Homozygotes in GnomAdExome at 2 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TTN	NM_001267550.2	c.48953T>C	p.Ile16318Thr	missense_variant	261/363	ENST00000589042.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TTN	ENST00000589042.5	c.48953T>C	p.Ile16318Thr	missense_variant	261/363	5	NM_001267550.2	P1
TTN-AS1	ENST00000659121.1	n.502+16880A>G		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.000955 AC: 145 AN: 151794 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000242

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000789

Gnomad ASJ AF: 0.0110

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000417

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.00110

Gnomad OTH AF: 0.00240

GnomAD3 exomes AF: 0.00122 AC: 302 AN: 247762 Hom.: 2 AF XY: 0.00127 AC XY: 171 AN XY: 134428

Gnomad AFR exome AF: 0.000194

Gnomad AMR exome AF: 0.00111

Gnomad ASJ exome AF: 0.00997

Gnomad EAS exome AF: 0.0000565

Gnomad SAS exome AF: 0.000425

Gnomad FIN exome AF: 0.0000931

Gnomad NFE exome AF: 0.00122

Gnomad OTH exome AF: 0.00133

GnomAD4 exome AF: 0.00104 AC: 1513 AN: 1460444 Hom.: 8 Cov.: 34 AF XY: 0.00108 AC XY: 786 AN XY: 726532

Gnomad4 AFR exome AF: 0.000269

Gnomad4 AMR exome AF: 0.00119

Gnomad4 ASJ exome AF: 0.00954

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000592

Gnomad4 FIN exome AF: 0.0000562

Gnomad4 NFE exome AF: 0.000958

Gnomad4 OTH exome AF: 0.00124

GnomAD4 genome AF: 0.000941 AC: 143 AN: 151912 Hom.: 0 Cov.: 32 AF XY: 0.000984 AC XY: 73 AN XY: 74216

Gnomad4 AFR AF: 0.000217

Gnomad4 AMR AF: 0.000788

Gnomad4 ASJ AF: 0.0110

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000417

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00110

Gnomad4 OTH AF: 0.00237

Alfa AF: 0.00169 Hom.: 2

Bravo AF: 0.000948

TwinsUK AF: 0.00108 AC: 4

ALSPAC AF: 0.00104 AC: 4

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.00182 AC: 15

ExAC AF: 0.00122 AC: 148

Asia WGS AF: 0.00115 AC: 4 AN: 3478

EpiCase AF: 0.00224

EpiControl AF: 0.00237

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:6 Benign:13

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:4

Benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 04, 2020	This variant is associated with the following publications: (PMID: 28144010, 27488758) -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jul 10, 2015	- -
Likely benign, criteria provided, single submitter	research	Biesecker Lab/Clinical Genomics Section, National Institutes of Health	Jun 24, 2013	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Feb 06, 2018	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2024	TTN: BS1, BS2 -

not specified Uncertain:1 Benign:3

Uncertain significance, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Nov 15, 2016	Variant classified as Uncertain Significance - Favor Benign. The p.Ile13750Thr v ariant in TTN has been identified by our laboratory in several individuals with various types of cardiomyopathy, did not segregate with disease in 1 relative wi th HCM, and has been identified in 0.2% (119/66356) of European chromosomes, inc luding 1 homozygote, by the Exome Aggregation Consortium (ExAC, http://exac.broa dinstitute.org; dbSNP rs72677243). Computational prediction tools and conservati on analysis suggest that the p.Ile13750Thr variant may impact the protein, thoug h this information is not predictive enough to determine pathogenicity. In summa ry, while the clinical significance of the p.Ile13750Thr variant is uncertain, i ts frequency suggests that it is more likely to be benign. -
Likely benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Mar 09, 2015	- -
Likely benign, criteria provided, single submitter	clinical testing	Al Jalila Children's Genomics Center, Al Jalila Childrens Speciality Hospital	Dec 12, 2019	- -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Dec 04, 2022	- -

Tibial muscular dystrophy Uncertain:1 Benign:1

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	May 08, 2017	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. -
Uncertain significance, no assertion criteria provided	clinical testing	Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics	Jul 07, 2014	The observed variant c.22334T>C (p.I7445T) is reported in 1000 Genomes and ExAC databases with a minor allele frequency of 0.0004 and 0.0012 respectively. The in silico prediction of the above variant is disease causing by MutationTaster2, tolerated by SIFT and probably damaging by PolyPhen2. -

Cardiomyopathy Benign:2

Benign, criteria provided, single submitter	clinical testing	CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	Jun 24, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Center for Advanced Laboratory Medicine, UC San Diego Health, University of California San Diego	Apr 01, 2019	- -

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

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

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

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

May 08, 2017

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. -

Cardiovascular phenotype Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 07, 2013

There is insufficient or conflicting evidence for classification of this alteration. -

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

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jan 29, 2024

- -

Dilated cardiomyopathy 1G Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

May 08, 2017

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). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to rule this variant out of causing disease. Therefore, this variant is classified as benign. -

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

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

May 08, 2017

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.91
BayesDel_addAF	Benign	-0.095	T
BayesDel_noAF	Uncertain	0.040
Cadd	Benign	20
Dann	Benign	0.85
Eigen	Pathogenic	0.89
Eigen_PC	Pathogenic	0.75
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.92	D;D;D;.;D;D;D
M_CAP	Uncertain	0.11	D
MetaRNN	Benign	0.0084	T;T;T;T;T;T;T
MetaSVM	Uncertain	0.76	D
MutationTaster	Benign	1.0	D;D;D;D;D;D
PrimateAI	Uncertain	0.62	T
PROVEAN	Uncertain	-3.6	D;D;.;.;D;D;.
REVEL	Pathogenic	0.75
Sift	Uncertain	0.0010	D;D;.;.;D;D;.
Polyphen		0.99	.;.;.;D;.;.;D
Vest4		0.54
MVP		0.87
MPC		0.45
ClinPred		0.40	T
GERP RS		5.6

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

Publications

LitVar

Other links and lift over

dbSNP: rs72677243; hg19: chr2-179479288; COSMIC: COSV60286115; COSMIC: COSV60286115;