2-178751752-G-A

Variant names:

• chr2-178751752-G-A
• rs141407971
• NM_001267550.2:c.11311+1372C>T

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS1

The NM_001267550.2(TTN):​c.11311+1372C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00034 in 1,613,038 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 Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0018 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00018 (1 hom.)
• Consequence: TTN NM_001267550.2 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.887
• Publications: 4 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 -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.007868826).
• BP6: Variant 2-178751752-G-A is Benign according to our data. Variant chr2-178751752-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 47729.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00184 (280/151974) while in subpopulation AFR AF = 0.00603 (250/41484). AF 95% confidence interval is 0.00541. There are 0 homozygotes in GnomAd4. There are 138 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

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.11311+1372C>T		intron	N/A	NP_001254479.2
	TTN	NM_133379.5		c.10648C>T	p.Arg3550Trp	missense	Exon 46 of 46	NP_596870.2
	TTN	NM_001256850.1		c.10360+1372C>T		intron	N/A	NP_001243779.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TTN	ENST00000589042.5	TSL:5 MANE Select	c.11311+1372C>T		intron	N/A	ENSP00000467141.1
	TTN	ENST00000446966.2	TSL:1	c.11311+1372C>T		intron	N/A	ENSP00000408004.2
	TTN	ENST00000436599.2	TSL:1	c.11035+1372C>T		intron	N/A	ENSP00000405517.2

Frequencies

GnomAD3 genomes AF: 0.00185 AC: 281 AN: 151856 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00604

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00158

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000945

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00191

GnomAD2 exomes AF: 0.000424 AC: 106 AN: 250078 AF XY: 0.000348

Gnomad AFR exome AF: 0.00585

Gnomad AMR exome AF: 0.000116

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000218

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000266

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000184 AC: 269 AN: 1461064 Hom.: 1 Cov.: 39 AF XY: 0.000169 AC XY: 123 AN XY: 726820

African (AFR) AF: 0.00583 AC: 195 AN: 33440

American (AMR) AF: 0.000381 AC: 17 AN: 44652

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26092

East Asian (EAS) AF: 0.000126 AC: 5 AN: 39658

South Asian (SAS) AF: 0.00 AC: 0 AN: 86204

European-Finnish (FIN) AF: 0.0000187 AC: 1 AN: 53388

Middle Eastern (MID) AF: 0.000174 AC: 1 AN: 5758

European-Non Finnish (NFE) AF: 0.0000243 AC: 27 AN: 1111526

Other (OTH) AF: 0.000381 AC: 23 AN: 60346

GnomAD4 genome AF: 0.00184 AC: 280 AN: 151974 Hom.: 0 Cov.: 32 AF XY: 0.00186 AC XY: 138 AN XY: 74280

African (AFR) AF: 0.00603 AC: 250 AN: 41484

American (AMR) AF: 0.00151 AC: 23 AN: 15238

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3462

East Asian (EAS) AF: 0.000194 AC: 1 AN: 5158

South Asian (SAS) AF: 0.00 AC: 0 AN: 4818

European-Finnish (FIN) AF: 0.0000945 AC: 1 AN: 10578

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

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 67918

Other (OTH) AF: 0.00189 AC: 4 AN: 2112

Alfa AF: 0.000827 Hom.: 1

Bravo AF: 0.00211

ESP6500AA AF: 0.00545 AC: 24

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.000552 AC: 67

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00

EpiControl AF: 0.000119

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

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

Dec 05, 2016

Eurofins Ntd Llc (ga)

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Jul 08, 2014

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.

Apr 03, 2012

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Arg3550Trp in exon 45A of TTN: This variant is not expected to have clinical sig nificance because it has been identified in 0.45% (17/3738) of African American chromosomes from a broad population by the NHLBI Exome Sequencing Project (http: //evs.gs.washington.edu/EVS/; dbSNP rs141407971). Arg3550Trp in exon 45A of TT N (rs141407971, allele frequency = 0.45%, 17/3738) **

not provided Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Oct 16, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.47	T
BayesDel_noAF	Benign	-0.44
CADD	Benign	12
DANN	Uncertain	0.99
Eigen	Benign	-0.25
Eigen_PC	Benign	-0.42
FATHMM_MKL	Benign	0.16	N
LIST_S2	Benign	0.73	T
M_CAP	Benign	0.022	T
MetaRNN	Benign	0.0079	T
MetaSVM	Benign	-0.59	T
PhyloP100		0.89
PROVEAN	Benign	-1.4	N
REVEL	Benign	0.24
Sift	Benign	0.18	T
Sift4G	Uncertain	0.0090	D
Polyphen		1.0	D
Vest4		0.27
MVP		0.48
ClinPred		0.041	T
GERP RS		-1.4
Mutation Taster		=92/8	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: rs141407971; hg19: chr2-179616479; COSMIC: COSV59934991; COSMIC: COSV59934991;