rs200204761

chr2-178739264-T-G

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 1P and 13B. PP2 BP4_Strong BP6 BS1 BS2

The NM_001267550.2(TTN):c.13969A>C(p.Asn4657His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00153 in 1,610,242 control chromosomes in the GnomAD database, including 33 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/17 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 0.00091 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0016 (32 hom.)
• Consequence: TTN NM_001267550.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:9
• Conservation: PhyloP100: 3.45

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]

LOC124906101 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• PP2: Missense variant where missense usually causes diseases, TTN
• BP4: Computational evidence support a benign effect (MetaRNN=0.006801218).
• BP6: Variant 2-178739264-T-G is Benign according to our data. Variant chr2-178739264-T-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 47843.We mark this variant Likely_benign, oryginal submissions are: {Benign=5, Uncertain_significance=2}. Variant chr2-178739264-T-G is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.000912 (139/152336) while in subpopulation SAS AF= 0.0157 (76/4830). AF 95% confidence interval is 0.0129. There are 1 homozygotes in gnomad4. There are 92 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome at 13 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TTN	NM_001267550.2	c.13969A>C	p.Asn4657His	missense_variant	48/363	ENST00000589042.5
LOC124906101	XR_007087319.1			downstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TTN	ENST00000589042.5	c.13969A>C	p.Asn4657His	missense_variant	48/363	5	NM_001267550.2	P1
TTN-AS1	ENST00000659121.1	n.1133+971T>G		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.000900 AC: 137 AN: 152218 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000965

Gnomad AMI AF: 0.00219

Gnomad AMR AF: 0.000393

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0155

Gnomad FIN AF: 0.000470

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000647

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.00275 AC: 679 AN: 247146 Hom.: 13 AF XY: 0.00363 AC XY: 487 AN XY: 134072

Gnomad AFR exome AF: 0.000129

Gnomad AMR exome AF: 0.000320

Gnomad ASJ exome AF: 0.00111

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0178

Gnomad FIN exome AF: 0.0000938

Gnomad NFE exome AF: 0.000875

Gnomad OTH exome AF: 0.00251

GnomAD4 exome AF: 0.00159 AC: 2318 AN: 1457906 Hom.: 32 Cov.: 31 AF XY: 0.00212 AC XY: 1533 AN XY: 724562

Gnomad4 AFR exome AF: 0.000120

Gnomad4 AMR exome AF: 0.000336

Gnomad4 ASJ exome AF: 0.000923

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0170

Gnomad4 FIN exome AF: 0.0000188

Gnomad4 NFE exome AF: 0.000623

Gnomad4 OTH exome AF: 0.00141

GnomAD4 genome AF: 0.000912 AC: 139 AN: 152336 Hom.: 1 Cov.: 32 AF XY: 0.00124 AC XY: 92 AN XY: 74488

Gnomad4 AFR AF: 0.0000962

Gnomad4 AMR AF: 0.000392

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.0157

Gnomad4 FIN AF: 0.000470

Gnomad4 NFE AF: 0.000647

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.000836 Hom.: 1

Bravo AF: 0.000518

TwinsUK AF: 0.00108 AC: 4

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000607 AC: 5

ExAC AF: 0.00311 AC: 376

Asia WGS AF: 0.00318 AC: 11 AN: 3476

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:9

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Uncertain:1 Benign:5

Benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 02, 2016	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. -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 19, 2014	The Asn4419His variant in TTN has been identified by our laboratory in 3 individ uals with cardiomyopathy (1 with DCM and 2 with HCM). It has also been identifie d in 5/8238 European American chromosomes by the NHLBI Exome Sequencing Project (http://evs.gs.washington.edu/EVS; dbSNP rs200204761). Computational predictions are limited or unavailable for this variant. Additional information is needed t o fully assess the clinical significance of this variant. -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

research

Biesecker Lab/Clinical Genomics Section, National Institutes of Health

Jun 24, 2013

- -

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

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 30, 2024

- -

Cardiomyopathy Benign:1

Benign, criteria provided, single submitter

clinical testing

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

Feb 27, 2018

- -

Hypertrophic cardiomyopathy Benign:1

Benign, criteria provided, single submitter

clinical testing

Center for Advanced Laboratory Medicine, UC San Diego Health, University of California San Diego

Jun 15, 2018

- -

Cardiovascular phenotype Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 12, 2019

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.47	T
BayesDel_noAF	Benign	-0.43
Cadd	Benign	19
Dann	Benign	0.86
Eigen	Uncertain	0.29
Eigen_PC	Uncertain	0.30
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.83	T;T;.;T;T;T
MetaRNN	Benign	0.0068	T;T;T;T;T;T
MetaSVM	Benign	-0.62	T
MutationTaster	Benign	1.0	D;N;N;N;N;N
PrimateAI	Benign	0.44	T
PROVEAN	Uncertain	-2.8	D;.;.;D;D;.
REVEL	Benign	0.22
Sift	Benign	0.057	T;.;.;T;T;.
Vest4		0.21
MVP		0.27
MPC		0.27
ClinPred		0.071	T
GERP RS		3.2

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: rs200204761; hg19: chr2-179603991; COSMIC: COSV59900364; COSMIC: COSV59900364;