rs201213901

Variant names:

• chr2-178607935-G-A
• rs201213901
• NM_001267550.2:c.52852C>T

Your query was ambiguous. Multiple possible variants found:

• chr2-178607935-G-A
• chr2-178607935-G-T

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_001267550.2(TTN):​c.52852C>T​(p.Arg17618Cys) variant causes a missense change. The variant allele was found at a frequency of 0.00133 in 1,612,904 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R17618H) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00083 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0014 (4 hom.)
• Consequence: TTN NM_001267550.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:9 B:18
• Conservation: PhyloP100: 5.36
• Publications: 9 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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.04911211).
• BP6: Variant 2-178607935-G-A is Benign according to our data. Variant chr2-178607935-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 47066.
• BS1: Variant frequency is greater than expected in population nfe. GnomAdExome4 allele frequency = 0.00138 (2012/1460928) while in subpopulation NFE AF = 0.00173 (1925/1111376). AF 95% confidence interval is 0.00167. There are 4 homozygotes in GnomAdExome4. There are 943 alleles in the male GnomAdExome4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 4 AD,AR gene

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.52852C>T	p.Arg17618Cys	missense	Exon 276 of 363	NP_001254479.2
	TTN	NM_001256850.1		c.47929C>T	p.Arg15977Cys	missense	Exon 226 of 313	NP_001243779.1
	TTN	NM_133378.4		c.45148C>T	p.Arg15050Cys	missense	Exon 225 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.52852C>T	p.Arg17618Cys	missense	Exon 276 of 363	ENSP00000467141.1
	TTN	ENST00000446966.2	TSL:1	c.52696C>T	p.Arg17566Cys	missense	Exon 274 of 361	ENSP00000408004.2
	TTN	ENST00000436599.2	TSL:1	c.52576C>T	p.Arg17526Cys	missense	Exon 274 of 361	ENSP00000405517.2

Frequencies

GnomAD3 genomes AF: 0.000830 AC: 126 AN: 151858 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000314

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000657

Gnomad ASJ AF: 0.000577

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000472

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00155

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000985 AC: 245 AN: 248616 AF XY: 0.000956

Gnomad AFR exome AF: 0.000323

Gnomad AMR exome AF: 0.0000580

Gnomad ASJ exome AF: 0.0000995

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000371

Gnomad NFE exome AF: 0.00200

Gnomad OTH exome AF: 0.000663

GnomAD4 exome AF: 0.00138 AC: 2012 AN: 1460928 Hom.: 4 Cov.: 32 AF XY: 0.00130 AC XY: 943 AN XY: 726768

African (AFR) AF: 0.000269 AC: 9 AN: 33426

American (AMR) AF: 0.0000224 AC: 1 AN: 44704

Ashkenazi Jewish (ASJ) AF: 0.000153 AC: 4 AN: 26110

East Asian (EAS) AF: 0.00 AC: 0 AN: 39600

South Asian (SAS) AF: 0.00 AC: 0 AN: 86238

European-Finnish (FIN) AF: 0.000487 AC: 26 AN: 53394

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5760

European-Non Finnish (NFE) AF: 0.00173 AC: 1925 AN: 1111376

Other (OTH) AF: 0.000779 AC: 47 AN: 60320

GnomAD4 genome AF: 0.000829 AC: 126 AN: 151976 Hom.: 0 Cov.: 32 AF XY: 0.000768 AC XY: 57 AN XY: 74264

African (AFR) AF: 0.000313 AC: 13 AN: 41520

American (AMR) AF: 0.0000656 AC: 1 AN: 15250

Ashkenazi Jewish (ASJ) AF: 0.000577 AC: 2 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5118

South Asian (SAS) AF: 0.00 AC: 0 AN: 4816

European-Finnish (FIN) AF: 0.000472 AC: 5 AN: 10594

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00155 AC: 105 AN: 67892

Other (OTH) AF: 0.00 AC: 0 AN: 2114

Alfa AF: 0.00122 Hom.: 0

Bravo AF: 0.000744

TwinsUK AF: 0.00162 AC: 6

ALSPAC AF: 0.00208 AC: 8

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.00191 AC: 16

ExAC AF: 0.00122 AC: 148

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	5	7	not provided (12)
-	1	4	not specified (5)
-	1	-	Autosomal recessive limb-girdle muscular dystrophy type 2J (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	Primary dilated cardiomyopathy;C0878544:Cardiomyopathy (1)
-	-	1	Tibial muscular dystrophy (1)
-	-	1	TTN-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.29
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Benign	-0.16
CADD	Uncertain	24
DANN	Benign	0.90
Eigen	Pathogenic	0.91
Eigen_PC	Pathogenic	0.89
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.97	D
M_CAP	Benign	0.018	T
MetaRNN	Benign	0.049	T
MetaSVM	Uncertain	-0.22	T
MutationAssessor	Uncertain	2.6	M
PhyloP100		5.4
PrimateAI	Uncertain	0.57	T
PROVEAN	Pathogenic	-6.0	D
REVEL	Uncertain	0.49
Sift	Uncertain	0.0010	D
Polyphen		1.0	D
Vest4		0.55
MVP		0.69
MPC		0.54
ClinPred		0.11	T
GERP RS		6.0
Mutation Taster		=96/4	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs201213901; hg19: chr2-179472662; COSMIC: COSV60103932; COSMIC: COSV60103932;