rs1060501430

chr14-23397592-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM2 PP2 BP4

The NM_002471.4(MYH6):c.1913G>C(p.Gly638Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: MYH6 NM_002471.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.02

Genes affected

MYH6 (HGNC:7576): (myosin heavy chain 6) Cardiac muscle myosin is a hexamer consisting of two heavy chain subunits, two light chain subunits, and two regulatory subunits. This gene encodes the alpha heavy chain subunit of cardiac myosin. The gene is located approximately 4kb downstream of the gene encoding the beta heavy chain subunit of cardiac myosin. Mutations in this gene cause familial hypertrophic cardiomyopathy and atrial septal defect 3. [provided by RefSeq, Feb 2017]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, MYH6
• BP4: Computational evidence support a benign effect (MetaRNN=0.42394328).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MYH6	NM_002471.4	c.1913G>C	p.Gly638Ala	missense_variant	16/39	ENST00000405093.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYH6	ENST00000405093.9	c.1913G>C	p.Gly638Ala	missense_variant	16/39	5	NM_002471.4	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Hypertrophic cardiomyopathy 14 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Apr 11, 2016

Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies. In summary, this variant is a novel missense change that is not predicted to affect protein function. There is no indication that it causes disease, but the available evidence is currently insufficient to prove that conclusively. Therefore, it has been classified as a Variant of Uncertain Significance. This variant is not present in population databases (ExAC no frequency) and has not been reported in the literature in individuals with a MYH6-related disease. This sequence change replaces glycine with alanine at codon 638 of the MYH6 protein (p.Gly638Ala). The glycine residue is weakly conserved and there is a small physicochemical difference between glycine and alanine. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.097
BayesDel_addAF	Uncertain	0.028	T
BayesDel_noAF	Benign	-0.20
Cadd	Uncertain	24
Dann	Uncertain	0.99
DEOGEN2	Uncertain	0.71	D;D
Eigen	Uncertain	0.24
Eigen_PC	Uncertain	0.30
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.78	T;.
M_CAP	Benign	0.058	D
MetaRNN	Benign	0.42	T;T
MetaSVM	Uncertain	0.31	D
MutationAssessor	Benign	1.5	L;L
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.62	T
PROVEAN	Benign	-2.3	N;N
REVEL	Uncertain	0.41
Sift	Benign	0.079	T;T
Sift4G	Benign	0.15	T;T
Polyphen		0.32	B;B
Vest4		0.45
MutPred		0.44		Gain of catalytic residue at K640 (P = 0.0013);Gain of catalytic residue at K640 (P = 0.0013);
MVP		0.85
MPC		0.49
ClinPred		0.71	D
GERP RS		4.3
Varity_R		0.24
gMVP		0.29

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1060501430; hg19: chr14-23866801;