2-178647040-GTATATATATA-GTATATATA

Variant names:

• chr2-178647040-GTA-G
• rs10580462
• NM_001267550.2:c.40222+22_40222+23delTA

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

The NM_001267550.2(TTN):​c.40222+22_40222+23delTA variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.233 in 697,118 control chromosomes in the GnomAD database, including 3,591 homozygotes. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.16 (3309 hom., cov: 21)
  • Exomes 𝑓: 0.25 (282 hom.)
• Consequence: TTN NM_001267550.2 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 0.194
• 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]

LOC124906100 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -16 ACMG points.

• BP6: Variant 2-178647040-GTA-G is Benign according to our data. Variant chr2-178647040-GTA-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 192211.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.38 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TTN	NM_001267550.2	c.40222+22_40222+23delTA		intron_variant	Intron 215 of 362	ENST00000589042.5	NP_001254479.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TTN	ENST00000589042.5	c.40222+22_40222+23delTA		intron_variant	Intron 215 of 362	5	NM_001267550.2	ENSP00000467141.1

Frequencies

GnomAD3 genomes AF: 0.158 AC: 22513 AN: 142842 Hom.: 3286 Cov.: 21

Gnomad AFR AF: 0.385

Gnomad AMI AF: 0.0500

Gnomad AMR AF: 0.194

Gnomad ASJ AF: 0.0398

Gnomad EAS AF: 0.0328

Gnomad SAS AF: 0.179

Gnomad FIN AF: 0.0935

Gnomad MID AF: 0.0884

Gnomad NFE AF: 0.0359

Gnomad OTH AF: 0.127

GnomAD2 exomes AF: 0.388 AC: 5946 AN: 15314 AF XY: 0.389

Gnomad AFR exome AF: 0.469

Gnomad AMR exome AF: 0.448

Gnomad ASJ exome AF: 0.362

Gnomad EAS exome AF: 0.367

Gnomad FIN exome AF: 0.372

Gnomad NFE exome AF: 0.407

Gnomad OTH exome AF: 0.426

GnomAD4 exome AF: 0.252 AC: 139575 AN: 554210 Hom.: 282 AF XY: 0.256 AC XY: 70479 AN XY: 275132

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.409 AC: 5069 AN: 12382

American (AMR) AF: 0.374 AC: 2570 AN: 6866

Ashkenazi Jewish (ASJ) AF: 0.283 AC: 2621 AN: 9270

East Asian (EAS) AF: 0.287 AC: 5192 AN: 18090

South Asian (SAS) AF: 0.306 AC: 3085 AN: 10088

European-Finnish (FIN) AF: 0.321 AC: 8084 AN: 25164

Middle Eastern (MID) AF: 0.294 AC: 521 AN: 1770

European-Non Finnish (NFE) AF: 0.236 AC: 105540 AN: 446724

Other (OTH) AF: 0.289 AC: 6893 AN: 23856

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.158 AC: 22589 AN: 142908 Hom.: 3309 Cov.: 21 AF XY: 0.164 AC XY: 11330 AN XY: 69288

African (AFR) AF: 0.385 AC: 15284 AN: 39664

American (AMR) AF: 0.195 AC: 2786 AN: 14288

Ashkenazi Jewish (ASJ) AF: 0.0398 AC: 134 AN: 3366

East Asian (EAS) AF: 0.0331 AC: 161 AN: 4864

South Asian (SAS) AF: 0.178 AC: 788 AN: 4432

European-Finnish (FIN) AF: 0.0935 AC: 799 AN: 8550

Middle Eastern (MID) AF: 0.0889 AC: 24 AN: 270

European-Non Finnish (NFE) AF: 0.0359 AC: 2322 AN: 64642

Other (OTH) AF: 0.127 AC: 247 AN: 1952

Alfa AF: 0.0115 Hom.: 16

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

-

Clinical Genetics, Academic Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Benign

Review Status: no assertion criteria provided

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

- -

-

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not provided Benign:2

Aug 10, 2019

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

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

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.19
Mutation Taster		=100/0	polymorphism (auto)

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: rs10580462; hg19: chr2-179511767; COSMIC: COSV60438288; COSMIC: COSV60438288;