rs191699632

Variant names:

• chr2-178637393-C-T
• rs191699632
• NM_001267550.2:c.40903G>A

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4_Strong BP6

The NM_001267550.2(TTN):​c.40903G>A​(p.Ala13635Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000515 in 1,475,716 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00027 (0 hom., cov: 31)
  • Exomes 𝑓: 0.000026 (0 hom.)
• Consequence: TTN NM_001267550.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:5
• Conservation: PhyloP100: 2.05
• Publications: 1 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 -5 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.01984787).
• BP6: Variant 2-178637393-C-T is Benign according to our data. Variant chr2-178637393-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 166074.

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.40903G>A	p.Ala13635Thr	missense	Exon 224 of 363	NP_001254479.2	Q8WZ42-12
	TTN	NM_001256850.1		c.35980G>A	p.Ala11994Thr	missense	Exon 174 of 313	NP_001243779.1	Q8WZ42-1
	TTN	NM_133378.4		c.33199G>A	p.Ala11067Thr	missense	Exon 173 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.40903G>A	p.Ala13635Thr	missense	Exon 224 of 363	ENSP00000467141.1	Q8WZ42-12
	TTN	ENST00000446966.2	TSL:1	c.40747G>A	p.Ala13583Thr	missense	Exon 222 of 361	ENSP00000408004.2	A0A1B0GXE3
	TTN	ENST00000436599.2	TSL:1	c.40627G>A	p.Ala13543Thr	missense	Exon 222 of 361	ENSP00000405517.2	A0A0C4DG59

Frequencies

GnomAD3 genomes AF: 0.000270 AC: 41 AN: 151574 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.000895

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000198

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.000481

GnomAD2 exomes AF: 0.0000640 AC: 10 AN: 156128 AF XY: 0.0000465

Gnomad AFR exome AF: 0.000954

Gnomad AMR exome AF: 0.0000623

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000130

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000264 AC: 35 AN: 1324024 Hom.: 0 Cov.: 28 AF XY: 0.0000321 AC XY: 21 AN XY: 653750

African (AFR) AF: 0.000991 AC: 27 AN: 27246

American (AMR) AF: 0.0000390 AC: 1 AN: 25658

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 22658

East Asian (EAS) AF: 0.00 AC: 0 AN: 31768

South Asian (SAS) AF: 0.00 AC: 0 AN: 60184

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49758

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5384

European-Non Finnish (NFE) AF: 0.00000286 AC: 3 AN: 1047148

Other (OTH) AF: 0.0000738 AC: 4 AN: 54220

GnomAD4 genome AF: 0.000270 AC: 41 AN: 151692 Hom.: 0 Cov.: 31 AF XY: 0.000297 AC XY: 22 AN XY: 74082

African (AFR) AF: 0.000893 AC: 37 AN: 41448

American (AMR) AF: 0.000197 AC: 3 AN: 15206

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

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

South Asian (SAS) AF: 0.00 AC: 0 AN: 4794

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10500

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67846

Other (OTH) AF: 0.000476 AC: 1 AN: 2102

Alfa AF: 0.0000918 Hom.: 0

Bravo AF: 0.000366

ESP6500AA AF: 0.00110 AC: 4

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000116 AC: 14

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	2	not provided (3)
-	1	2	not specified (3)
-	1	-	Autosomal recessive limb-girdle muscular dystrophy type 2J;C1858763:Dilated cardiomyopathy 1G (1)
-	-	1	Cardiovascular phenotype (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.084
BayesDel_addAF	Benign	-0.36	T
BayesDel_noAF	Benign	-0.36
CADD	Benign	21
DANN	Benign	0.91
Eigen	Benign	0.017
Eigen_PC	Benign	0.18
FATHMM_MKL	Uncertain	0.83	D
LIST_S2	Benign	0.72	T
M_CAP	Uncertain	0.092	D
MetaRNN	Benign	0.020	T
MetaSVM	Benign	-0.69	T
MutationAssessor	Benign	2.0	M
PhyloP100		2.1
PrimateAI	Uncertain	0.51	T
PROVEAN	Benign	-1.8	N
REVEL	Benign	0.094
Sift	Uncertain	0.010	D
Polyphen		0.020	B
Vest4		0.18
MVP		0.19
MPC		0.082
ClinPred		0.056	T
GERP RS		5.4
Mutation Taster		=85/15	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: rs191699632; hg19: chr2-179502120; COSMIC: COSV100631452; COSMIC: COSV100631452;