2-178647040-GTATATATATA-GTATATATATATA

Variant names:

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

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+23dupTA variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0538 in 720,988 control chromosomes in the GnomAD database, including 285 homozygotes. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.059 (262 hom., cov: 21)
  • Exomes 𝑓: 0.053 (23 hom.)
• Consequence: TTN NM_001267550.2 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -0.212
• 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-G-GTA is Benign according to our data. Variant chr2-178647040-G-GTA is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 192212.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0667 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+23dupTA		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+23_40222+24insTA		intron_variant	Intron 215 of 362	5	NM_001267550.2	ENSP00000467141.1

Frequencies

GnomAD3 genomes AF: 0.0590 AC: 8438 AN: 143074 Hom.: 262 Cov.: 21

Gnomad AFR AF: 0.0291

Gnomad AMI AF: 0.0422

Gnomad AMR AF: 0.0644

Gnomad ASJ AF: 0.128

Gnomad EAS AF: 0.0453

Gnomad SAS AF: 0.0699

Gnomad FIN AF: 0.0896

Gnomad MID AF: 0.0850

Gnomad NFE AF: 0.0684

Gnomad OTH AF: 0.0731

GnomAD2 exomes AF: 0.0796 AC: 1219 AN: 15314 AF XY: 0.0790

Gnomad AFR exome AF: 0.0175

Gnomad AMR exome AF: 0.0172

Gnomad ASJ exome AF: 0.111

Gnomad EAS exome AF: 0.0167

Gnomad FIN exome AF: 0.0921

Gnomad NFE exome AF: 0.0674

Gnomad OTH exome AF: 0.0490

GnomAD4 exome AF: 0.0526 AC: 30375 AN: 577846 Hom.: 23 Cov.: 0 AF XY: 0.0538 AC XY: 15452 AN XY: 287300

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

African (AFR) AF: 0.0271 AC: 341 AN: 12592

American (AMR) AF: 0.0450 AC: 323 AN: 7182

Ashkenazi Jewish (ASJ) AF: 0.0814 AC: 786 AN: 9652

East Asian (EAS) AF: 0.0479 AC: 915 AN: 19116

South Asian (SAS) AF: 0.0551 AC: 571 AN: 10356

European-Finnish (FIN) AF: 0.0658 AC: 1825 AN: 27718

Middle Eastern (MID) AF: 0.0565 AC: 104 AN: 1842

European-Non Finnish (NFE) AF: 0.0522 AC: 24265 AN: 464578

Other (OTH) AF: 0.0502 AC: 1245 AN: 24810

⚠️ 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: 0.0589 AC: 8437 AN: 143142 Hom.: 262 Cov.: 21 AF XY: 0.0602 AC XY: 4182 AN XY: 69426

African (AFR) AF: 0.0292 AC: 1159 AN: 39696

American (AMR) AF: 0.0642 AC: 919 AN: 14310

Ashkenazi Jewish (ASJ) AF: 0.128 AC: 430 AN: 3372

East Asian (EAS) AF: 0.0452 AC: 220 AN: 4864

South Asian (SAS) AF: 0.0693 AC: 307 AN: 4430

European-Finnish (FIN) AF: 0.0896 AC: 773 AN: 8624

Middle Eastern (MID) AF: 0.0852 AC: 23 AN: 270

European-Non Finnish (NFE) AF: 0.0684 AC: 4427 AN: 64744

Other (OTH) AF: 0.0726 AC: 142 AN: 1956

Alfa AF: 0.0250 Hom.: 16

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Jun 24, 2013

Biesecker Lab/Clinical Genomics Section, National Institutes of Health

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: research

- -

-

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

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 18, 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

Aug 15, 2024

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		-0.21
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs10580462; hg19: chr2-179511767;