14-23386369-G-C

Variant names:

• chr14-23386369-G-C
• NM_002471.4:c.4905C>G

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PP3_Moderate BS2

The NM_002471.4(MYH6):​c.4905C>G​(p.Asn1635Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000116 in 1,461,846 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. N1635N) has been classified as Benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000012 (0 hom.)
• Consequence: MYH6 NM_002471.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.35

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 Likely_benign. Variant got -2 ACMG points.

• PP3: MetaRNN computational evidence supports a deleterious effect, 0.879
• BS2: High AC in GnomAdExome4 at 17 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYH6	NM_002471.4	c.4905C>G	p.Asn1635Lys	missense_variant	Exon 33 of 39	ENST00000405093.9	NP_002462.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MYH6	ENST00000405093.9	c.4905C>G	p.Asn1635Lys	missense_variant	Exon 33 of 39	5	NM_002471.4	ENSP00000386041.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.0000116 AC: 17 AN: 1461846 Hom.: 0 Cov.: 71 AF XY: 0.0000124 AC XY: 9 AN XY: 727226

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000153

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.75
BayesDel_addAF	Benign	0.010	T
BayesDel_noAF	Benign	-0.22
CADD	Benign	19
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.66	D;D
Eigen	Uncertain	0.26
Eigen_PC	Benign	0.083
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Benign	0.81	T;.
M_CAP	Uncertain	0.10	D
MetaRNN	Pathogenic	0.88	D;D
MetaSVM	Uncertain	0.38	D
MutationAssessor	Uncertain	2.8	M;M
PrimateAI	Uncertain	0.55	T
PROVEAN	Uncertain	-3.5	D;D
REVEL	Uncertain	0.42
Sift	Uncertain	0.0010	D;D
Sift4G	Uncertain	0.0090	D;D
Polyphen		0.97	D;D
Vest4		0.81
MutPred		0.65		Gain of ubiquitination at N1635 (P = 0.0075);Gain of ubiquitination at N1635 (P = 0.0075);
MVP		0.92
MPC		0.90
ClinPred		0.98	D
GERP RS		2.6
Varity_R		0.37
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

No publications associated with this variant yet.

Other links and lift over

hg19: chr14-23855578;