2-178647040-GTATATATATA-GTATATATATATATATA

Variant names:

• chr2-178647040-G-GTATATA
• rs10580462
• NM_001267550.2:c.40222+18_40222+23dupTATATA

Variant summary

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

The NM_001267550.2(TTN):​c.40222+18_40222+23dupTATATA variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00148 in 731,142 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 0.0013 (1 hom., cov: 21)
  • Exomes 𝑓: 0.0015 (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 afr. GnomAd4 allele frequency = 0.0013 (187/143340) while in subpopulation AFR AF = 0.0036 (143/39724). AF 95% confidence interval is 0.00312. There are 1 homozygotes in GnomAd4. There are 98 alleles in the male GnomAd4 subpopulation. Median coverage is 21. This position passed quality control check.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001267550.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TTN	NM_001267550.2	MANE Select	c.40222+18_40222+23dupTATATA		intron	N/A	NP_001254479.2
	TTN	NM_001256850.1		c.35375-1016_35375-1011dupTATATA		intron	N/A	NP_001243779.1
	TTN	NM_133378.4		c.32594-1016_32594-1011dupTATATA		intron	N/A	NP_596869.4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TTN	ENST00000589042.5	TSL:5 MANE Select	c.40222+23_40222+24insTATATA		intron	N/A	ENSP00000467141.1
	TTN	ENST00000446966.2	TSL:1	c.40222+23_40222+24insTATATA		intron	N/A	ENSP00000408004.2
	TTN	ENST00000436599.2	TSL:1	c.39946+23_39946+24insTATATA		intron	N/A	ENSP00000405517.2

Frequencies

GnomAD3 genomes AF: 0.00131 AC: 187 AN: 143274 Hom.: 1 Cov.: 21

Gnomad AFR AF: 0.00361

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000419

Gnomad ASJ AF: 0.000296

Gnomad EAS AF: 0.00307

Gnomad SAS AF: 0.000224

Gnomad FIN AF: 0.000347

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000170

Gnomad OTH AF: 0.00360

GnomAD2 exomes AF: 0.00340 AC: 52 AN: 15314 AF XY: 0.00318

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0167

Gnomad FIN exome AF: 0.00508

Gnomad NFE exome AF: 0.00120

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00153 AC: 897 AN: 587802 Hom.: 0 Cov.: 0 AF XY: 0.00162 AC XY: 474 AN XY: 292246

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

African (AFR) AF: 0.00150 AC: 19 AN: 12694

American (AMR) AF: 0.00221 AC: 16 AN: 7252

Ashkenazi Jewish (ASJ) AF: 0.00174 AC: 17 AN: 9788

East Asian (EAS) AF: 0.00872 AC: 168 AN: 19270

South Asian (SAS) AF: 0.000858 AC: 9 AN: 10494

European-Finnish (FIN) AF: 0.00414 AC: 116 AN: 27998

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

European-Non Finnish (NFE) AF: 0.00107 AC: 505 AN: 473270

Other (OTH) AF: 0.00179 AC: 45 AN: 25172

⚠️ 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: 0.00130 AC: 187 AN: 143340 Hom.: 1 Cov.: 21 AF XY: 0.00141 AC XY: 98 AN XY: 69544

African (AFR) AF: 0.00360 AC: 143 AN: 39724

American (AMR) AF: 0.000419 AC: 6 AN: 14328

Ashkenazi Jewish (ASJ) AF: 0.000296 AC: 1 AN: 3374

East Asian (EAS) AF: 0.00308 AC: 15 AN: 4868

South Asian (SAS) AF: 0.000225 AC: 1 AN: 4444

European-Finnish (FIN) AF: 0.000347 AC: 3 AN: 8656

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

European-Non Finnish (NFE) AF: 0.000170 AC: 11 AN: 64838

Other (OTH) AF: 0.00358 AC: 7 AN: 1958

Alfa AF: 0.00 Hom.: 16

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

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;