2-178647040-GTATATATATA-GTATATATATATATATATATA

Position:

• chr2-178647040-GTATATATATA-GTATATATATATATATATATA

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BS1

The NM_001267550.2(TTN):​c.40222+23_40222+24insTATATATATA 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

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

Verdict is Likely_benign. Variant got -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 male gnomad4 subpopulation. Median coverage is 21. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TTN	NM_001267550.2	c.40222+23_40222+24insTATATATATA		intron_variant		ENST00000589042.5	NP_001254479.2
LOC124906100	XR_007087318.1	n.2185+2552_2185+2561dup		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TTN	ENST00000589042.5	c.40222+23_40222+24insTATATATATA		intron_variant		5	NM_001267550.2	ENSP00000467141	P1
TTN-AS1	ENST00000659121.1	n.502+49372_502+49381dup		intron_variant, non_coding_transcript_variant

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

Gnomad4 AFR exome AF: 0.0000788

Gnomad4 AMR exome AF: 0.000551

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00176

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.000641

Gnomad4 NFE exome AF: 0.000279

Gnomad4 OTH exome AF: 0.000199

GnomAD4 genome AF: 0.00104 AC: 149 AN: 143342 Hom.: 1 Cov.: 21 AF XY: 0.00106 AC XY: 74 AN XY: 69548

Gnomad4 AFR AF: 0.000302

Gnomad4 AMR AF: 0.00126

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00925

Gnomad4 SAS AF: 0.00113

Gnomad4 FIN AF: 0.000462

Gnomad4 NFE AF: 0.000972

Gnomad4 OTH AF: 0.00102

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs10580462; hg19: chr2-179511767;