rs377289817

chr2-178611471-G-Cchr2-178611471-G-T

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 1P and 5B. PP2 BP4_Strong BP6

The NM_001267550.2(TTN):c.50758C>G(p.Pro16920Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0001 in 1,612,930 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00059 (1 hom., cov: 33)
  • Exomes 𝑓: 0.000050 (0 hom.)
• Consequence: TTN NM_001267550.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:6
• Conservation: PhyloP100: 7.98

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 Likely_benign. Variant got -4 ACMG points.

• PP2: Missense variant where missense usually causes diseases, TTN
• BP4: Computational evidence support a benign effect (MetaRNN=0.023157).
• BP6: Variant 2-178611471-G-C is Benign according to our data. Variant chr2-178611471-G-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 229449.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=6, Uncertain_significance=3}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TTN	NM_001267550.2	c.50758C>G	p.Pro16920Ala	missense_variant	269/363	ENST00000589042.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TTN	ENST00000589042.5	c.50758C>G	p.Pro16920Ala	missense_variant	269/363	5	NM_001267550.2	P1
TTN-AS1	ENST00000659121.1	n.502+13790G>C		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.000586 AC: 89 AN: 151952 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.00203

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000197

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.000956

GnomAD3 exomes AF: 0.000190 AC: 47 AN: 247258 Hom.: 0 AF XY: 0.000179 AC XY: 24 AN XY: 134116

Gnomad AFR exome AF: 0.00240

Gnomad AMR exome AF: 0.000290

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000500 AC: 73 AN: 1460860 Hom.: 0 Cov.: 33 AF XY: 0.0000454 AC XY: 33 AN XY: 726752

Gnomad4 AFR exome AF: 0.00162

Gnomad4 AMR exome AF: 0.000313

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000829

GnomAD4 genome AF: 0.000585 AC: 89 AN: 152070 Hom.: 1 Cov.: 33 AF XY: 0.000525 AC XY: 39 AN XY: 74310

Gnomad4 AFR AF: 0.00202

Gnomad4 AMR AF: 0.000197

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.000946

Alfa AF: 0.0000282 Hom.: 0

Bravo AF: 0.000514

ESP6500AA AF: 0.00124 AC: 5

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000248 AC: 30

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3 Benign:6

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:2 Benign:2

Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Aug 28, 2018	- -
Likely benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Jan 03, 2023	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Dec 04, 2019	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 18, 2021	- -

not specified Uncertain:1 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	May 14, 2015	Variant classified as Uncertain Significance - Favor Benign. The p.Pro14352Ala v ariant in TTN has not been previously reported in individuals with cardiomyopath y, but has been identified in 0.2% (22/9750) of African chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs377289817 ). Computational prediction tools and conservation analysis do not provide stro ng support for or against an impact to the protein. In summary, while the clinic al significance of the p.Pro14352Ala variant is uncertain, its frequency suggest s that it is more likely to be benign. -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Dec 04, 2023	Variant summary: TTN c.43054C>G (p.Pro14352Ala) results in a non-conservative amino acid change located in the A band region of the encoded protein sequence. Four of four in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00019 in 247258 control chromosomes, predominantly at a frequency of 0.0024 within the African or African-American subpopulation in the gnomAD database. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 6 fold of the estimated maximal expected allele frequency for a pathogenic variant in TTN causing Dilated Cardiomyopathy phenotype (0.00039), strongly suggesting that the variant is a benign polymorphism found primarily in populations of African or African-American origin. Seven submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 and classifed the variant as likely benign (n=4) or VUS (n=3). Based on the evidence outlined above, the variant was classified as likely benign. -

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

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

Primary dilated cardiomyopathy Benign:1

Likely benign, criteria provided, single submitter

clinical testing

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

Feb 07, 2018

- -

Cardiovascular phenotype Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 10, 2019

This alteration is classified as likely 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	0.16
BayesDel_addAF	Benign	-0.30	T
BayesDel_noAF	Benign	-0.21
Cadd	Benign	20
Dann	Benign	0.87
Eigen	Pathogenic	0.91
Eigen_PC	Pathogenic	0.90
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.90	D;D;D;.;D;D;D
M_CAP	Benign	0.013	T
MetaRNN	Benign	0.023	T;T;T;T;T;T;T
MetaSVM	Uncertain	0.010	D
MutationTaster	Benign	1.0	D;D;D;D;D;D
PrimateAI	Uncertain	0.65	T
PROVEAN	Pathogenic	-5.4	D;D;.;.;D;D;.
REVEL	Uncertain	0.45
Sift	Benign	0.051	T;D;.;.;D;D;.
Polyphen		1.0	.;.;.;D;.;.;D
Vest4		0.46
MVP		0.44
MPC		0.46
ClinPred		0.083	T
GERP RS		6.0

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: rs377289817; hg19: chr2-179476198;