chr2-178698872-G-A

Variant names:

• chr2-178698872-G-A
• rs397517534
• NM_001267550.2:c.30725C>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The ENST00000589042.5(TTN):​c.30725C>T​(p.Ala10242Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000137 in 145,828 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000014 (0 hom., cov: 31)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: TTN ENST00000589042.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.33
• Publications: 0 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]

LOC124906100 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.08583343).

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000589042.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TTN	NM_001267550.2	MANE Select	c.30725C>T	p.Ala10242Val	missense	Exon 112 of 363	NP_001254479.2
	TTN	NM_001256850.1		c.29774C>T	p.Ala9925Val	missense	Exon 110 of 313	NP_001243779.1
	TTN	NM_133378.4		c.26993C>T	p.Ala8998Val	missense	Exon 109 of 312	NP_596869.4

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TTN	ENST00000589042.5	TSL:5 MANE Select	c.30725C>T	p.Ala10242Val	missense	Exon 112 of 363	ENSP00000467141.1
	TTN	ENST00000446966.2	TSL:1	c.30725C>T	p.Ala10242Val	missense	Exon 112 of 361	ENSP00000408004.2
	TTN	ENST00000436599.2	TSL:1	c.30449C>T	p.Ala10150Val	missense	Exon 110 of 361	ENSP00000405517.2

Frequencies

GnomAD3 genomes AF: 0.0000137 AC: 2 AN: 145828 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.0000509

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1389036 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 684482

African (AFR) AF: 0.00 AC: 0 AN: 31366

American (AMR) AF: 0.00 AC: 0 AN: 35282

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25096

East Asian (EAS) AF: 0.00 AC: 0 AN: 35884

South Asian (SAS) AF: 0.00 AC: 0 AN: 75730

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 46060

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5598

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1076278

Other (OTH) AF: 0.00 AC: 0 AN: 57742

GnomAD4 genome AF: 0.0000137 AC: 2 AN: 145828 Hom.: 0 Cov.: 31 AF XY: 0.0000142 AC XY: 1 AN XY: 70474

African (AFR) AF: 0.0000509 AC: 2 AN: 39258

American (AMR) AF: 0.00 AC: 0 AN: 14436

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3454

East Asian (EAS) AF: 0.00 AC: 0 AN: 5040

South Asian (SAS) AF: 0.00 AC: 0 AN: 4694

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 8642

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 302

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67114

Other (OTH) AF: 0.00 AC: 0 AN: 1978

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.099
BayesDel_addAF	Benign	-0.092	T
BayesDel_noAF	Benign	-0.37
CADD	Benign	16
DANN	Benign	0.93
DEOGEN2	Benign	0.037	T
Eigen	Benign	-0.55
Eigen_PC	Benign	-0.48
FATHMM_MKL	Benign	0.63	D
LIST_S2	Benign	0.72	T
M_CAP	Benign	0.017	T
MetaRNN	Benign	0.086	T
MetaSVM	Benign	-0.88	T
PhyloP100		2.3
PrimateAI	Benign	0.31	T
PROVEAN	Benign	-1.3	N
REVEL	Benign	0.089
Sift	Benign	0.12	T
Polyphen		0.0	B
Vest4		0.18
MutPred		0.35		Gain of sheet (P = 0.0043)
MVP		0.15
MPC		0.083
ClinPred		0.072	T
GERP RS		3.7
Mutation Taster		=81/19	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: rs397517534; hg19: chr2-179563599;