2-178647040-GTATATATATA-GTATATATATATATATATATA

Variant names:

• chr2-178647040-G-GTATATATATA
• rs10580462
• NM_001267550.2:c.40222+14_40222+23dupTATATATATA

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BS1

The NM_001267550.2(TTN):​c.40222+14_40222+23dupTATATATATA variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000469 in 731,392 control chromosomes in the GnomAD database, including 1 homozygotes. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.0010 (1 hom., cov: 21)
  • Exomes 𝑓: 0.00033 (0 hom.)
• Consequence: TTN NM_001267550.2 intron
• Clinical Significance: Not reported in ClinVar
• 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: Likely_benign. The variant received -4 ACMG points.

• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.00104 (149/143342) while in subpopulation EAS AF = 0.00925 (45/4866). AF 95% confidence interval is 0.0071. There are 1 homozygotes in GnomAd4. There are 74 alleles in the male GnomAd4 subpopulation. Median coverage is 21. This position passed quality control check.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TTN	NM_001267550.2	c.40222+14_40222+23dupTATATATATA		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+24insTATATATATA		intron_variant	Intron 215 of 362	5	NM_001267550.2	ENSP00000467141.1

Frequencies

GnomAD3 genomes AF: 0.00104 AC: 149 AN: 143276 Hom.: 1 Cov.: 21

Gnomad AFR AF: 0.000303

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00126

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00922

Gnomad SAS AF: 0.00112

Gnomad FIN AF: 0.000462

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000972

Gnomad OTH AF: 0.00103

GnomAD4 exome AF: 0.000330 AC: 194 AN: 588050 Hom.: 0 Cov.: 0 AF XY: 0.000345 AC XY: 101 AN XY: 292366

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

African (AFR) AF: 0.0000788 AC: 1 AN: 12696

American (AMR) AF: 0.000551 AC: 4 AN: 7258

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 9790

East Asian (EAS) AF: 0.00176 AC: 34 AN: 19306

South Asian (SAS) AF: 0.00 AC: 0 AN: 10496

European-Finnish (FIN) AF: 0.000641 AC: 18 AN: 28088

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 1866

European-Non Finnish (NFE) AF: 0.000279 AC: 132 AN: 473374

Other (OTH) AF: 0.000199 AC: 5 AN: 25176

⚠️ 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: 0.00104 AC: 149 AN: 143342 Hom.: 1 Cov.: 21 AF XY: 0.00106 AC XY: 74 AN XY: 69548

African (AFR) AF: 0.000302 AC: 12 AN: 39728

American (AMR) AF: 0.00126 AC: 18 AN: 14326

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3374

East Asian (EAS) AF: 0.00925 AC: 45 AN: 4866

South Asian (SAS) AF: 0.00113 AC: 5 AN: 4444

European-Finnish (FIN) AF: 0.000462 AC: 4 AN: 8656

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 270

European-Non Finnish (NFE) AF: 0.000972 AC: 63 AN: 64840

Other (OTH) AF: 0.00102 AC: 2 AN: 1958

Alfa AF: 0.00 Hom.: 16

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.21
Mutation Taster		=100/0	polymorphism

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;