rs202094100

Variant names:

• chr2-178613870-C-A
• rs202094100
• NM_001267550.2:c.49413G>T

Your query was ambiguous. Multiple possible variants found:

• chr2-178613870-C-A
• chr2-178613870-C-G
• chr2-178613870-C-T

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 0P and 1B. BP6

The NM_001267550.2(TTN):​c.49413G>T​(p.Trp16471Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000584 in 1,611,738 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00038 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00061 (0 hom.)
• Consequence: TTN NM_001267550.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:12 B:6
• Conservation: PhyloP100: 7.86
• Publications: 13 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: Likely_benign. The variant received -1 ACMG points.

• BP6: Variant 2-178613870-C-A is Benign according to our data. Variant chr2-178613870-C-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 47030.

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.49413G>T	p.Trp16471Cys	missense	Exon 263 of 363	NP_001254479.2
	TTN	NM_001256850.1		c.44490G>T	p.Trp14830Cys	missense	Exon 213 of 313	NP_001243779.1
	TTN	NM_133378.4		c.41709G>T	p.Trp13903Cys	missense	Exon 212 of 312	NP_596869.4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TTN	ENST00000589042.5	TSL:5 MANE Select	c.49413G>T	p.Trp16471Cys	missense	Exon 263 of 363	ENSP00000467141.1
	TTN	ENST00000446966.2	TSL:1	c.49257G>T	p.Trp16419Cys	missense	Exon 261 of 361	ENSP00000408004.2
	TTN	ENST00000436599.2	TSL:1	c.49137G>T	p.Trp16379Cys	missense	Exon 261 of 361	ENSP00000405517.2

Frequencies

GnomAD3 genomes AF: 0.000375 AC: 57 AN: 151912 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000966

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000377

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000692

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000348 AC: 86 AN: 247226 AF XY: 0.000388

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000146

Gnomad ASJ exome AF: 0.000100

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000421

Gnomad NFE exome AF: 0.000589

Gnomad OTH exome AF: 0.000834

GnomAD4 exome AF: 0.000606 AC: 884 AN: 1459826 Hom.: 0 Cov.: 32 AF XY: 0.000603 AC XY: 438 AN XY: 726134

African (AFR) AF: 0.000150 AC: 5 AN: 33382

American (AMR) AF: 0.000135 AC: 6 AN: 44568

Ashkenazi Jewish (ASJ) AF: 0.0000768 AC: 2 AN: 26042

East Asian (EAS) AF: 0.00 AC: 0 AN: 39612

South Asian (SAS) AF: 0.0000582 AC: 5 AN: 85950

European-Finnish (FIN) AF: 0.000694 AC: 37 AN: 53326

Middle Eastern (MID) AF: 0.000348 AC: 2 AN: 5752

European-Non Finnish (NFE) AF: 0.000717 AC: 797 AN: 1110910

Other (OTH) AF: 0.000498 AC: 30 AN: 60284

GnomAD4 genome AF: 0.000375 AC: 57 AN: 151912 Hom.: 0 Cov.: 32 AF XY: 0.000351 AC XY: 26 AN XY: 74170

African (AFR) AF: 0.0000966 AC: 4 AN: 41410

American (AMR) AF: 0.000131 AC: 2 AN: 15226

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3464

East Asian (EAS) AF: 0.00 AC: 0 AN: 5124

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.000377 AC: 4 AN: 10610

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.000692 AC: 47 AN: 67932

Other (OTH) AF: 0.00 AC: 0 AN: 2088

Alfa AF: 0.000617 Hom.: 0

Bravo AF: 0.000370

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.000778 AC: 3

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000839 AC: 7

ExAC AF: 0.000389 AC: 47

EpiCase AF: 0.000929

EpiControl AF: 0.000951

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	5	1	not provided (6)
-	-	2	not specified (2)
-	1	-	Autosomal recessive limb-girdle muscular dystrophy type 2J (1)
-	1	-	Autosomal recessive limb-girdle muscular dystrophy type 2J;C1838244:Tibial muscular dystrophy;C1858763:Dilated cardiomyopathy 1G;C1861065:Hypertrophic cardiomyopathy 9;C1863599:Myopathy, myofibrillar, 9, with early respiratory failure;C2673677:Early-onset myopathy with fatal cardiomyopathy (1)
-	1	-	Autosomal recessive limb-girdle muscular dystrophy type 2J;C1858763:Dilated cardiomyopathy 1G (1)
-	-	1	Cardiomyopathy (1)
-	1	-	Cardiovascular phenotype (1)
-	1	-	Dilated cardiomyopathy 1G (1)
-	1	-	Early-onset myopathy with fatal cardiomyopathy (1)
-	-	1	Myopathy, myofibrillar, 9, with early respiratory failure (1)
-	-	1	Tibial muscular dystrophy (1)
-	1	-	TTN-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Benign	0.0084	T
BayesDel_noAF	Pathogenic	0.19
CADD	Uncertain	24
DANN	Benign	0.94
Eigen	Pathogenic	1.2
Eigen_PC	Pathogenic	1.1
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.95	D
M_CAP	Uncertain	0.19	D
MetaRNN	Uncertain	0.59	D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	4.1	H
PhyloP100		7.9
PrimateAI	Pathogenic	0.83	D
PROVEAN	Pathogenic	-10	D
REVEL	Pathogenic	0.74
Sift	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.65
MutPred		0.84		Gain of disorder (P = 0.0222)
MVP		0.91
MPC		0.58
ClinPred		0.27	T
GERP RS		6.1
Mutation Taster		=71/29	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs202094100; hg19: chr2-179478597; COSMIC: COSV104642406;