14-23407138-C-G

Position:

• chr14-23407138-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP2

The NM_002471.4(MYH6):​c.86G>C​(p.Arg29Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R29Q) has been classified as Benign.

• Frequency: Genomes: not found (cov: 33)
• Consequence: MYH6 NM_002471.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.72

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]

MYH6 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), MYH6. . Gene score misZ 0.85843 (greater than the threshold 3.09). Trascript score misZ 4.1282 (greater than threshold 3.09). GenCC has associacion of gene with dilated cardiomyopathy, hypertrophic cardiomyopathy, Keppen-Lubinsky syndrome, atrial septal defect 3, familial isolated dilated cardiomyopathy, hypertrophic cardiomyopathy 14.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MYH6	NM_002471.4	c.86G>C	p.Arg29Pro	missense_variant	3/39	ENST00000405093.9	NP_002462.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MYH6	ENST00000405093.9	c.86G>C	p.Arg29Pro	missense_variant	3/39	5	NM_002471.4	ENSP00000386041.3
MYH6	ENST00000557461.2	n.153G>C		non_coding_transcript_exon_variant	3/14	5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ExAC AF: 0.00000824 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Pathogenic	0.16	D
BayesDel_noAF	Uncertain	0.0
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.49	T;T
Eigen	Benign	-0.18
Eigen_PC	Benign	-0.087
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Benign	0.84	T;.
M_CAP	Benign	0.062	D
MetaRNN	Uncertain	0.51	D;D
MetaSVM	Uncertain	-0.23	T
MutationAssessor	Uncertain	2.9	M;M
PrimateAI	Uncertain	0.62	T
PROVEAN	Uncertain	-2.7	D;D
REVEL	Uncertain	0.56
Sift	Benign	0.055	T;T
Sift4G	Benign	0.093	T;T
Polyphen		0.0030	B;B
Vest4		0.67
MutPred		0.44		Gain of catalytic residue at R29 (P = 0);Gain of catalytic residue at R29 (P = 0);
MVP		0.87
MPC		0.53
ClinPred		0.68	D
GERP RS		3.5
Varity_R		0.48
gMVP		0.78

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: rs150574114; hg19: chr14-23876347;