2-178647040-GTATATATATA-GTATATATATATATATATA

Variant names:

• chr2-178647040-G-GTATATATA
• rs10580462
• NM_001267550.2:c.40222+16_40222+23dupTATATATA

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP6_Moderate BA1

The NM_001267550.2(TTN):​c.40222+16_40222+23dupTATATATA variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00685 in 730,910 control chromosomes in the GnomAD database, including 47 homozygotes. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.018 (44 hom., cov: 21)
  • Exomes 𝑓: 0.0042 (3 hom.)
• Consequence: TTN NM_001267550.2 intron
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• 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 -10 ACMG points.

• BP6: Variant 2-178647040-G-GTATATATA is Benign according to our data. Variant chr2-178647040-G-GTATATATA is described in ClinVar as Likely_benign. ClinVar VariationId is 1223854.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0735 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TTN	NM_001267550.2	c.40222+16_40222+23dupTATATATA		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+24insTATATATA		intron_variant	Intron 215 of 362	5	NM_001267550.2	ENSP00000467141.1

Frequencies

GnomAD3 genomes AF: 0.0178 AC: 2555 AN: 143214 Hom.: 45 Cov.: 21

Gnomad AFR AF: 0.00404

Gnomad AMI AF: 0.0308

Gnomad AMR AF: 0.0198

Gnomad ASJ AF: 0.0187

Gnomad EAS AF: 0.0802

Gnomad SAS AF: 0.00605

Gnomad FIN AF: 0.0346

Gnomad MID AF: 0.00340

Gnomad NFE AF: 0.0196

Gnomad OTH AF: 0.0185

GnomAD2 exomes AF: 0.0132 AC: 202 AN: 15314 AF XY: 0.0117

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00833

Gnomad FIN exome AF: 0.0216

Gnomad NFE exome AF: 0.00361

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00418 AC: 2459 AN: 587630 Hom.: 3 Cov.: 0 AF XY: 0.00426 AC XY: 1246 AN XY: 292154

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

African (AFR) AF: 0.000394 AC: 5 AN: 12696

American (AMR) AF: 0.00358 AC: 26 AN: 7256

Ashkenazi Jewish (ASJ) AF: 0.00225 AC: 22 AN: 9784

East Asian (EAS) AF: 0.0161 AC: 310 AN: 19266

South Asian (SAS) AF: 0.00124 AC: 13 AN: 10496

European-Finnish (FIN) AF: 0.0154 AC: 428 AN: 27874

Middle Eastern (MID) AF: 0.00107 AC: 2 AN: 1864

European-Non Finnish (NFE) AF: 0.00330 AC: 1562 AN: 473236

Other (OTH) AF: 0.00362 AC: 91 AN: 25158

⚠️ 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: 0.0178 AC: 2551 AN: 143280 Hom.: 44 Cov.: 21 AF XY: 0.0181 AC XY: 1261 AN XY: 69508

African (AFR) AF: 0.00403 AC: 160 AN: 39722

American (AMR) AF: 0.0198 AC: 283 AN: 14314

Ashkenazi Jewish (ASJ) AF: 0.0187 AC: 63 AN: 3374

East Asian (EAS) AF: 0.0801 AC: 389 AN: 4858

South Asian (SAS) AF: 0.00563 AC: 25 AN: 4444

European-Finnish (FIN) AF: 0.0346 AC: 299 AN: 8640

Middle Eastern (MID) AF: 0.00370 AC: 1 AN: 270

European-Non Finnish (NFE) AF: 0.0196 AC: 1268 AN: 64824

Other (OTH) AF: 0.0184 AC: 36 AN: 1956

Alfa AF: 0.00710 Hom.: 16

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Aug 13, 2019

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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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;