chr14-23393767-G-C

Variant names:

• chr14-23393767-G-C
• rs368912844
• NM_002471.4:c.2827C>G

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_002471.4(MYH6):​c.2827C>G​(p.Arg943Gly) 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 pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: MYH6 NM_002471.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.60

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 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.881

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYH6	NM_002471.4	c.2827C>G	p.Arg943Gly	missense_variant	Exon 22 of 39	ENST00000405093.9	NP_002462.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MYH6	ENST00000405093.9	c.2827C>G	p.Arg943Gly	missense_variant	Exon 22 of 39	5	NM_002471.4	ENSP00000386041.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.88
BayesDel_addAF	Pathogenic	0.43	D
BayesDel_noAF	Pathogenic	0.39
CADD	Uncertain	24
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.75	D;D
Eigen	Pathogenic	0.78
Eigen_PC	Pathogenic	0.71
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Pathogenic	0.98	D;.
M_CAP	Uncertain	0.11	D
MetaRNN	Pathogenic	0.88	D;D
MetaSVM	Pathogenic	0.80	D
MutationAssessor	Pathogenic	3.8	H;H
PrimateAI	Pathogenic	0.88	D
PROVEAN	Pathogenic	-5.8	D;D
REVEL	Pathogenic	0.80
Sift	Uncertain	0.0010	D;D
Sift4G	Uncertain	0.017	D;D
Polyphen		1.0	D;D
Vest4		0.86
MutPred		0.42		Gain of ubiquitination at K941 (P = 0.0641);Gain of ubiquitination at K941 (P = 0.0641);
MVP		0.95
MPC		1.3
ClinPred		1.0	D
GERP RS		5.0
Varity_R		0.69
gMVP		0.88

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

Publications

LitVar

Other links and lift over

dbSNP: rs368912844; hg19: chr14-23862976;