rs2562836

Variant names:

• chr2-178715095-T-A
• rs2562836
• NM_001267550.2:c.26091A>T

Your query was ambiguous. Multiple possible variants found:

• chr2-178715095-T-A
• chr2-178715095-T-G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001267550.2(TTN):​c.26091A>T​(p.Leu8697Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.247 in 1,613,490 control chromosomes in the GnomAD database, including 58,221 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.31 (8278 hom., cov: 32)
  • Exomes 𝑓: 0.24 (49943 hom.)
• Consequence: TTN NM_001267550.2 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:22
• Conservation: PhyloP100: -1.36
• Publications: 19 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]

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.71).
• BP6: Variant 2-178715095-T-A is Benign according to our data. Variant chr2-178715095-T-A is described in ClinVar as Benign. ClinVar VariationId is 46773.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.632 is higher than 0.05.

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.26091A>T	p.Leu8697Leu	synonymous	Exon 90 of 363	NP_001254479.2	Q8WZ42-12
	TTN	NM_001256850.1		c.25140A>T	p.Leu8380Leu	synonymous	Exon 88 of 313	NP_001243779.1	Q8WZ42-1
	TTN	NM_133378.4		c.22359A>T	p.Leu7453Leu	synonymous	Exon 87 of 312	NP_596869.4	Q8WZ42-11

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TTN	ENST00000589042.5	TSL:5 MANE Select	c.26091A>T	p.Leu8697Leu	synonymous	Exon 90 of 363	ENSP00000467141.1	Q8WZ42-12
	TTN	ENST00000446966.2	TSL:1	c.26091A>T	p.Leu8697Leu	synonymous	Exon 90 of 361	ENSP00000408004.2	A0A1B0GXE3
	TTN	ENST00000436599.2	TSL:1	c.25815A>T	p.Leu8605Leu	synonymous	Exon 88 of 361	ENSP00000405517.2	A0A0C4DG59

Frequencies

GnomAD3 genomes AF: 0.305 AC: 46401 AN: 151916 Hom.: 8241 Cov.: 32

Gnomad AFR AF: 0.424

Gnomad AMI AF: 0.544

Gnomad AMR AF: 0.358

Gnomad ASJ AF: 0.203

Gnomad EAS AF: 0.651

Gnomad SAS AF: 0.430

Gnomad FIN AF: 0.205

Gnomad MID AF: 0.187

Gnomad NFE AF: 0.205

Gnomad OTH AF: 0.292

GnomAD2 exomes AF: 0.309 AC: 76774 AN: 248688 AF XY: 0.304

Gnomad AFR exome AF: 0.424

Gnomad AMR exome AF: 0.413

Gnomad ASJ exome AF: 0.199

Gnomad EAS exome AF: 0.670

Gnomad FIN exome AF: 0.203

Gnomad NFE exome AF: 0.203

Gnomad OTH exome AF: 0.267

GnomAD4 exome AF: 0.241 AC: 352175 AN: 1461456 Hom.: 49943 Cov.: 34 AF XY: 0.244 AC XY: 177485 AN XY: 727018

African (AFR) AF: 0.432 AC: 14442 AN: 33456

American (AMR) AF: 0.410 AC: 18346 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.200 AC: 5229 AN: 26128

East Asian (EAS) AF: 0.648 AC: 25740 AN: 39698

South Asian (SAS) AF: 0.418 AC: 36038 AN: 86246

European-Finnish (FIN) AF: 0.204 AC: 10888 AN: 53402

Middle Eastern (MID) AF: 0.268 AC: 1543 AN: 5766

European-Non Finnish (NFE) AF: 0.202 AC: 224114 AN: 1111678

Other (OTH) AF: 0.262 AC: 15835 AN: 60366

GnomAD4 genome AF: 0.306 AC: 46493 AN: 152034 Hom.: 8278 Cov.: 32 AF XY: 0.312 AC XY: 23174 AN XY: 74296

African (AFR) AF: 0.425 AC: 17620 AN: 41454

American (AMR) AF: 0.359 AC: 5477 AN: 15264

Ashkenazi Jewish (ASJ) AF: 0.203 AC: 703 AN: 3468

East Asian (EAS) AF: 0.651 AC: 3351 AN: 5150

South Asian (SAS) AF: 0.429 AC: 2071 AN: 4822

European-Finnish (FIN) AF: 0.205 AC: 2168 AN: 10592

Middle Eastern (MID) AF: 0.194 AC: 57 AN: 294

European-Non Finnish (NFE) AF: 0.205 AC: 13929 AN: 67968

Other (OTH) AF: 0.295 AC: 622 AN: 2112

Alfa AF: 0.228 Hom.: 1419

Bravo AF: 0.324

Asia WGS AF: 0.536 AC: 1864 AN: 3476

EpiCase AF: 0.200

EpiControl AF: 0.210

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	9	not specified (9)
-	-	2	Autosomal recessive limb-girdle muscular dystrophy type 2J (2)
-	-	2	Early-onset myopathy with fatal cardiomyopathy (2)
-	-	2	Myopathy, myofibrillar, 9, with early respiratory failure (2)
-	-	2	not provided (2)
-	-	2	Tibial muscular dystrophy (2)
-	-	1	Autosomal recessive limb-girdle muscular dystrophy type 2J;C1858763:Dilated cardiomyopathy 1G (1)
-	-	1	Cardiovascular phenotype (1)
-	-	1	Dilated cardiomyopathy 1G (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.71
CADD	Benign	1.6
DANN	Benign	0.73
PhyloP100		-1.4
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs2562836; hg19: chr2-179579822; COSMIC: COSV59966483; COSMIC: COSV59966483;