rs10580462

Variant names:

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

Your query was ambiguous. Multiple possible variants found:

• chr2-178647040-GTATATATATA-G
• chr2-178647040-GTATATATATA-GTA
• chr2-178647040-GTATATATATA-GTATA
• chr2-178647040-GTATATATATA-GTATATA
• chr2-178647040-GTATATATATA-GTATATATA
• chr2-178647040-GTATATATATA-GTATATATATATA
• chr2-178647040-GTATATATATA-GTATATATATATATA
• chr2-178647040-GTATATATATA-GTATATATATATATATA
• chr2-178647040-GTATATATATA-GTATATATATATATATATA
• chr2-178647040-GTATATATATA-GTATATATATATATATATATA
• chr2-178647040-GTATATATATA-GTATATATATATATATATATATA
• chr2-178647040-GTATATATATA-GTATATATATATATATATATATATA
• chr2-178647040-GTATATATATA-GTATATATATATATATATATATATATA
• chr2-178647040-GTATATATATA-GTATATATATATATATATATATATATATA
• chr2-178647040-GTATATATATA-GTATATATATATATATATATATATATATATA
• chr2-178647040-GTATATATATA-GTATATATATATATATATATATATATATATATA
• chr2-178647040-GTATATATATA-GTATATATATATATATATATATATATATATATATA
• chr2-178647040-GTATATATATA-GTATATATATATATATATATATATATATATATATATA
• chr2-178647040-GTATATATATA-GTATATATATATATATATATATATATATATATATATATA
• chr2-178647040-GTATATATATA-GTATATATATATATATATATATATATATATATATATATATATA

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP6_Moderate

The NM_001267550.2(TTN):​c.40222+14_40222+23delTATATATATA variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000273 in 731,396 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0000070 (0 hom., cov: 21)
  • Exomes 𝑓: 0.0000017 (0 hom.)
• Consequence: TTN NM_001267550.2 intron
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.346
• 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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP6: Variant 2-178647040-GTATATATATA-G is Benign according to our data. Variant chr2-178647040-GTATATATATA-G is described in ClinVar as Likely_benign. ClinVar VariationId is 2168350.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

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

Frequencies

GnomAD3 genomes AF: 0.00000698 AC: 1 AN: 143282 Hom.: 0 Cov.: 21

Gnomad AFR AF: 0.0000252

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000170 AC: 1 AN: 588114 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 292410

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

African (AFR) AF: 0.00 AC: 0 AN: 12696

American (AMR) AF: 0.00 AC: 0 AN: 7260

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 19322

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

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 28100

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

European-Non Finnish (NFE) AF: 0.00000211 AC: 1 AN: 473404

Other (OTH) AF: 0.00 AC: 0 AN: 25180

⚠️ 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: 0.00000698 AC: 1 AN: 143282 Hom.: 0 Cov.: 21 AF XY: 0.00 AC XY: 0 AN XY: 69468

African (AFR) AF: 0.0000252 AC: 1 AN: 39620

American (AMR) AF: 0.00 AC: 0 AN: 14314

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 4886

South Asian (SAS) AF: 0.00 AC: 0 AN: 4464

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 8656

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 64848

Other (OTH) AF: 0.00 AC: 0 AN: 1946

Alfa AF: 0.00 Hom.: 16

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

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

Oct 04, 2022

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		0.35

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;