rs191539637

Variant names:

• chr2-178611515-C-T
• rs191539637
• NM_001267550.2:c.50714G>A

Your query was ambiguous. Multiple possible variants found:

• chr2-178611515-C-T
• chr2-178611515-C-G

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_001267550.2(TTN):​c.50714G>A​(p.Arg16905His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000366 in 1,612,876 control chromosomes in the GnomAD database, including 1 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. R16905C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00053 (1 hom., cov: 33)
  • Exomes 𝑓: 0.00035 (0 hom.)
• Consequence: TTN NM_001267550.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:8 B:15
• Conservation: PhyloP100: 7.86
• Publications: 10 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 -4 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.03199315).

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.50714G>A	p.Arg16905His	missense	Exon 269 of 363	NP_001254479.2	Q8WZ42-12
	TTN	NM_001256850.1		c.45791G>A	p.Arg15264His	missense	Exon 219 of 313	NP_001243779.1	Q8WZ42-1
	TTN	NM_133378.4		c.43010G>A	p.Arg14337His	missense	Exon 218 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.50714G>A	p.Arg16905His	missense	Exon 269 of 363	ENSP00000467141.1	Q8WZ42-12
	TTN	ENST00000446966.2	TSL:1	c.50558G>A	p.Arg16853His	missense	Exon 267 of 361	ENSP00000408004.2	A0A1B0GXE3
	TTN	ENST00000436599.2	TSL:1	c.50438G>A	p.Arg16813His	missense	Exon 267 of 361	ENSP00000405517.2	A0A0C4DG59

Frequencies

GnomAD3 genomes AF: 0.000527 AC: 80 AN: 151862 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.0000966

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000656

Gnomad ASJ AF: 0.00288

Gnomad EAS AF: 0.000390

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00170

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000663

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000392 AC: 97 AN: 247328 AF XY: 0.000358

Gnomad AFR exome AF: 0.000194

Gnomad AMR exome AF: 0.0000580

Gnomad ASJ exome AF: 0.00250

Gnomad EAS exome AF: 0.000336

Gnomad FIN exome AF: 0.000975

Gnomad NFE exome AF: 0.000314

Gnomad OTH exome AF: 0.000665

GnomAD4 exome AF: 0.000350 AC: 511 AN: 1460896 Hom.: 0 Cov.: 33 AF XY: 0.000366 AC XY: 266 AN XY: 726760

African (AFR) AF: 0.000150 AC: 5 AN: 33414

American (AMR) AF: 0.0000671 AC: 3 AN: 44696

Ashkenazi Jewish (ASJ) AF: 0.00310 AC: 81 AN: 26116

East Asian (EAS) AF: 0.000101 AC: 4 AN: 39600

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86238

European-Finnish (FIN) AF: 0.00112 AC: 60 AN: 53386

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 0.000306 AC: 340 AN: 1111362

Other (OTH) AF: 0.000282 AC: 17 AN: 60320

GnomAD4 genome AF: 0.000526 AC: 80 AN: 151980 Hom.: 1 Cov.: 33 AF XY: 0.000458 AC XY: 34 AN XY: 74284

African (AFR) AF: 0.0000964 AC: 4 AN: 41510

American (AMR) AF: 0.0000655 AC: 1 AN: 15256

Ashkenazi Jewish (ASJ) AF: 0.00288 AC: 10 AN: 3470

East Asian (EAS) AF: 0.000391 AC: 2 AN: 5112

South Asian (SAS) AF: 0.00 AC: 0 AN: 4822

European-Finnish (FIN) AF: 0.00170 AC: 18 AN: 10594

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

European-Non Finnish (NFE) AF: 0.000663 AC: 45 AN: 67898

Other (OTH) AF: 0.00 AC: 0 AN: 2112

Alfa AF: 0.000638 Hom.: 0

Bravo AF: 0.000283

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000603 AC: 5

ExAC AF: 0.000381 AC: 46

EpiCase AF: 0.000546

EpiControl AF: 0.000119

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	3	6	not provided (9)
-	2	4	not specified (6)
-	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	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	-	-	Tip-toe gait (1)
-	-	1	TTN-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.22
BayesDel_addAF	Benign	-0.31	T
BayesDel_noAF	Benign	-0.23
CADD	Uncertain	24
DANN	Benign	0.95
Eigen	Pathogenic	0.82
Eigen_PC	Pathogenic	0.85
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.94	D
M_CAP	Benign	0.0096	T
MetaRNN	Benign	0.032	T
MetaSVM	Benign	-0.51	T
MutationAssessor	Benign	1.9	L
PhyloP100		7.9
PrimateAI	Uncertain	0.75	T
PROVEAN	Uncertain	-3.6	D
REVEL	Uncertain	0.39
Sift	Uncertain	0.0080	D
Polyphen		1.0	D
Vest4		0.41
MVP		0.31
MPC		0.52
ClinPred		0.047	T
GERP RS		6.0
Mutation Taster		=91/9	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: rs191539637; hg19: chr2-179476242;