2-178647040-GTATATATATA-GTATATATATATATA

Variant names:

• chr2-178647040-G-GTATA
• rs10580462
• NM_001267550.2:c.40222+20_40222+23dupTATA

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP6_Moderate BS1 BS2

The NM_001267550.2(TTN):​c.40222+20_40222+23dupTATA variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0065 in 730,512 control chromosomes in the GnomAD database, including 30 homozygotes. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.017 (29 hom., cov: 21)
  • Exomes 𝑓: 0.0039 (1 hom.)
• Consequence: TTN NM_001267550.2 intron
• Clinical Significance: Likely benign criteria provided, single submitter B:3
• 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-GTATA is Benign according to our data. Variant chr2-178647040-G-GTATA is described in ClinVar as Likely_benign. ClinVar VariationId is 1193112.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.0173 (2480/143300) while in subpopulation EAS AF = 0.0423 (206/4868). AF 95% confidence interval is 0.0376. There are 29 homozygotes in GnomAd4. There are 1251 alleles in the male GnomAd4 subpopulation. Median coverage is 21. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 29 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TTN	NM_001267550.2	c.40222+20_40222+23dupTATA		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+24insTATA		intron_variant	Intron 215 of 362	5	NM_001267550.2	ENSP00000467141.1

Frequencies

GnomAD3 genomes AF: 0.0173 AC: 2484 AN: 143234 Hom.: 30 Cov.: 21

Gnomad AFR AF: 0.0392

Gnomad AMI AF: 0.00227

Gnomad AMR AF: 0.00929

Gnomad ASJ AF: 0.0160

Gnomad EAS AF: 0.0426

Gnomad SAS AF: 0.00560

Gnomad FIN AF: 0.0176

Gnomad MID AF: 0.0102

Gnomad NFE AF: 0.00504

Gnomad OTH AF: 0.0149

GnomAD2 exomes AF: 0.0121 AC: 186 AN: 15314 AF XY: 0.0117

Gnomad AFR exome AF: 0.0175

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00230

Gnomad EAS exome AF: 0.0167

Gnomad FIN exome AF: 0.0185

Gnomad NFE exome AF: 0.00321

Gnomad OTH exome AF: 0.0196

GnomAD4 exome AF: 0.00386 AC: 2269 AN: 587212 Hom.: 1 Cov.: 0 AF XY: 0.00398 AC XY: 1162 AN XY: 291970

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

African (AFR) AF: 0.0147 AC: 186 AN: 12662

American (AMR) AF: 0.00345 AC: 25 AN: 7240

Ashkenazi Jewish (ASJ) AF: 0.00758 AC: 74 AN: 9768

East Asian (EAS) AF: 0.0187 AC: 359 AN: 19242

South Asian (SAS) AF: 0.00200 AC: 21 AN: 10484

European-Finnish (FIN) AF: 0.0124 AC: 346 AN: 27996

Middle Eastern (MID) AF: 0.00376 AC: 7 AN: 1862

European-Non Finnish (NFE) AF: 0.00240 AC: 1133 AN: 472814

Other (OTH) AF: 0.00469 AC: 118 AN: 25144

⚠️ 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: 0.0173 AC: 2480 AN: 143300 Hom.: 29 Cov.: 21 AF XY: 0.0180 AC XY: 1251 AN XY: 69516

African (AFR) AF: 0.0390 AC: 1550 AN: 39696

American (AMR) AF: 0.00928 AC: 133 AN: 14326

Ashkenazi Jewish (ASJ) AF: 0.0160 AC: 54 AN: 3374

East Asian (EAS) AF: 0.0423 AC: 206 AN: 4868

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

European-Finnish (FIN) AF: 0.0176 AC: 152 AN: 8648

Middle Eastern (MID) AF: 0.00741 AC: 2 AN: 270

European-Non Finnish (NFE) AF: 0.00504 AC: 327 AN: 64836

Other (OTH) AF: 0.0148 AC: 29 AN: 1958

Alfa AF: 0.00232 Hom.: 16

ClinVar

Significance: Likely benign

Submissions summary: Benign:3

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:2

Aug 21, 2019

GeneDx

Significance: Likely 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

- -

not specified Benign:1

-

Clinical Genetics, Academic Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

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;