NM_002471.4:c.4980C>G

Variant names:

• chr14-23386111-G-C
• rs382872
• NM_002471.4:c.4980C>G

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_002471.4(MYH6):​c.4980C>G​(p.Asp1660Glu) 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. Synonymous variant affecting the same amino acid position (i.e. D1660D) has been classified as Benign.

• Frequency: Genomes: not found (cov: 31)
• Consequence: MYH6 NM_002471.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.151
• Publications: 14 publications found

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 Gene-Disease associations (from GenCC):

• hypertrophic cardiomyopathy 14

  Inheritance: AD Classification: STRONG, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), PanelApp Australia, Laboratory for Molecular Medicine
• Keppen-Lubinsky syndrome

  Inheritance: AD Classification: MODERATE Submitted by: Illumina
• familial isolated dilated cardiomyopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• atrial septal defect 3

  Inheritance: AD Classification: LIMITED Submitted by: G2P
• dilated cardiomyopathy

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen
• hypertrophic cardiomyopathy

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.913

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYH6	NM_002471.4	c.4980C>G	p.Asp1660Glu	missense_variant	Exon 34 of 39	ENST00000405093.9	NP_002462.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MYH6	ENST00000405093.9	c.4980C>G	p.Asp1660Glu	missense_variant	Exon 34 of 39	5	NM_002471.4	ENSP00000386041.3

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 35

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.41
BayesDel_addAF	Benign	0.0032	T
BayesDel_noAF	Benign	-0.23
CADD	Benign	0.93
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.66	D;D
Eigen	Benign	-0.82
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.47	N
LIST_S2	Uncertain	0.96	D;.
M_CAP	Benign	0.081	D
MetaRNN	Pathogenic	0.91	D;D
MetaSVM	Benign	-0.35	T
MutationAssessor	Benign	1.5	L;L
PhyloP100		-0.15
PrimateAI	Uncertain	0.60	T
PROVEAN	Uncertain	-2.7	D;D
REVEL	Uncertain	0.44
Sift	Benign	0.049	D;D
Sift4G	Benign	0.66	T;T
Polyphen		1.0	D;D
Vest4		0.68
MutPred		0.46		Gain of MoRF binding (P = 0.2435);Gain of MoRF binding (P = 0.2435);
MVP		0.72
MPC		0.85
ClinPred		0.79	D
GERP RS		-5.3
Varity_R		0.11
gMVP		0.47
Mutation Taster		=76/24	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: rs382872; hg19: chr14-23855320;