rs200875815

Variant names:

• chr2-178769694-T-G
• rs200875815
• NM_001267550.2:c.8887A>C

Your query was ambiguous. Multiple possible variants found:

• chr2-178769694-T-G
• chr2-178769694-T-A
• chr2-178769694-T-C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BP6_Very_Strong

The NM_001267550.2(TTN):​c.8887A>C​(p.Thr2963Pro) variant causes a missense change. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. T2963T) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0021 (0 hom., cov: 32)
  • Exomes 𝑓: 0.023 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: TTN NM_001267550.2 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 5.89
• Publications: 18 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0024864674).
• BP6: Variant 2-178769694-T-G is Benign according to our data. Variant chr2-178769694-T-G is described in ClinVar as Benign. ClinVar VariationId is 137826.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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.8887A>C	p.Thr2963Pro	missense	Exon 37 of 363	NP_001254479.2	Q8WZ42-12
	TTN	NM_001256850.1		c.8887A>C	p.Thr2963Pro	missense	Exon 37 of 313	NP_001243779.1	Q8WZ42-1
	TTN	NM_133378.4		c.8887A>C	p.Thr2963Pro	missense	Exon 37 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.8887A>C	p.Thr2963Pro	missense	Exon 37 of 363	ENSP00000467141.1	Q8WZ42-12
	TTN	ENST00000446966.2	TSL:1	c.8887A>C	p.Thr2963Pro	missense	Exon 37 of 361	ENSP00000408004.2	A0A1B0GXE3
	TTN	ENST00000436599.2	TSL:1	c.8611A>C	p.Thr2871Pro	missense	Exon 35 of 361	ENSP00000405517.2	A0A0C4DG59

Frequencies

GnomAD3 genomes AF: 0.00205 AC: 309 AN: 151062 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000363

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000790

Gnomad ASJ AF: 0.00522

Gnomad EAS AF: 0.00292

Gnomad SAS AF: 0.000835

Gnomad FIN AF: 0.000571

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00344

Gnomad OTH AF: 0.00338

GnomAD2 exomes AF: 0.210 AC: 44503 AN: 211948 AF XY: 0.220

Gnomad AFR exome AF: 0.241

Gnomad AMR exome AF: 0.135

Gnomad ASJ exome AF: 0.172

Gnomad EAS exome AF: 0.183

Gnomad FIN exome AF: 0.299

Gnomad NFE exome AF: 0.227

Gnomad OTH exome AF: 0.135

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0234 AC: 33711 AN: 1442314 Hom.: 0 Cov.: 33 AF XY: 0.0284 AC XY: 20354 AN XY: 716000

African (AFR) AF: 0.0281 AC: 935 AN: 33294

American (AMR) AF: 0.0943 AC: 4015 AN: 42590

Ashkenazi Jewish (ASJ) AF: 0.0523 AC: 1327 AN: 25372

East Asian (EAS) AF: 0.0430 AC: 1684 AN: 39128

South Asian (SAS) AF: 0.0693 AC: 5753 AN: 83026

European-Finnish (FIN) AF: 0.0872 AC: 4217 AN: 48334

Middle Eastern (MID) AF: 0.0887 AC: 451 AN: 5086

European-Non Finnish (NFE) AF: 0.0129 AC: 14298 AN: 1105838

Other (OTH) AF: 0.0173 AC: 1031 AN: 59646

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.00207 AC: 313 AN: 151146 Hom.: 0 Cov.: 32 AF XY: 0.00256 AC XY: 189 AN XY: 73750

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

African (AFR) AF: 0.000387 AC: 16 AN: 41378

American (AMR) AF: 0.000790 AC: 12 AN: 15196

Ashkenazi Jewish (ASJ) AF: 0.00522 AC: 18 AN: 3446

East Asian (EAS) AF: 0.00273 AC: 14 AN: 5130

South Asian (SAS) AF: 0.00104 AC: 5 AN: 4788

European-Finnish (FIN) AF: 0.000571 AC: 6 AN: 10506

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 276

European-Non Finnish (NFE) AF: 0.00346 AC: 233 AN: 67420

Other (OTH) AF: 0.00430 AC: 9 AN: 2094

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00500 Hom.: 0

ExAC AF: 0.355 AC: 38310

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.25
BayesDel_addAF	Pathogenic	0.25	D
BayesDel_noAF	Uncertain	0.12
CADD	Benign	23
DANN	Benign	0.94
Eigen	Pathogenic	0.75
Eigen_PC	Pathogenic	0.73
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.92	D
MetaRNN	Benign	0.0025	T
MetaSVM	Uncertain	0.16	D
PhyloP100		5.9
PrimateAI	Uncertain	0.60	T
PROVEAN	Uncertain	-4.1	D
REVEL	Pathogenic	0.70
Sift	Benign	0.12	T
Sift4G	Uncertain	0.0090	D
Polyphen		1.0	D
Vest4		0.19
MPC		0.53
ClinPred		0.035	T
GERP RS		5.9
Mutation Taster		=84/16	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs200875815; hg19: chr2-179634421; COSMIC: COSV59871240; COSMIC: COSV59871240;