chr14-23386608-C-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PP2PP3BS2

The NM_002471.4(MYH6):​c.4666G>A​(p.Glu1556Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000341 in 1,464,722 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. E1556E) has been classified as Benign.

Frequency

Genomes: 𝑓 0.000061 ( 0 hom., cov: 31)
Exomes 𝑓: 0.000031 ( 0 hom. )

Consequence

MYH6
NM_002471.4 missense

Scores

9
8
2

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:3

Conservation

PhyloP100: 7.89
Variant links:
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

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.
PP3
MetaRNN computational evidence supports a deleterious effect, 0.806
BS2
High AC in GnomAd4 at 9 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
MYH6NM_002471.4 linkuse as main transcriptc.4666G>A p.Glu1556Lys missense_variant 33/39 ENST00000405093.9 NP_002462.2

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
MYH6ENST00000405093.9 linkuse as main transcriptc.4666G>A p.Glu1556Lys missense_variant 33/395 NM_002471.4 ENSP00000386041 P1

Frequencies

GnomAD3 genomes
AF:
0.0000608
AC:
9
AN:
148104
Hom.:
0
Cov.:
31
show subpopulations
Gnomad AFR
AF:
0.000147
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000134
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000149
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000842
AC:
21
AN:
249316
Hom.:
0
AF XY:
0.0000891
AC XY:
12
AN XY:
134678
show subpopulations
Gnomad AFR exome
AF:
0.000370
Gnomad AMR exome
AF:
0.000319
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.0000331
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000267
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000311
AC:
41
AN:
1316618
Hom.:
0
Cov.:
61
AF XY:
0.0000245
AC XY:
16
AN XY:
652200
show subpopulations
Gnomad4 AFR exome
AF:
0.000337
Gnomad4 AMR exome
AF:
0.000270
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000118
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000187
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.0000608
AC:
9
AN:
148104
Hom.:
0
Cov.:
31
AF XY:
0.0000691
AC XY:
5
AN XY:
72322
show subpopulations
Gnomad4 AFR
AF:
0.000147
Gnomad4 AMR
AF:
0.000134
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000149
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.000115
Hom.:
0
Bravo
AF:
0.0000907
ESP6500AA
AF:
0.000227
AC:
1
ESP6500EA
AF:
0.00
AC:
0
ExAC
AF:
0.0000824
AC:
10
EpiCase
AF:
0.00
EpiControl
AF:
0.0000593

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Hypertrophic cardiomyopathy 14 Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpDec 17, 2022In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt MYH6 protein function. ClinVar contains an entry for this variant (Variation ID: 537962). This variant has not been reported in the literature in individuals affected with MYH6-related conditions. This variant is present in population databases (rs148582147, gnomAD 0.03%), and has an allele count higher than expected for a pathogenic variant. This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 1556 of the MYH6 protein (p.Glu1556Lys). -
Atrial septal defect 3 Uncertain:1
Uncertain significance, criteria provided, single submitterresearchHudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for BiotechnologyOct 11, 2018ACMG codes: PP3, PP4 -
Cardiovascular phenotype Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsOct 13, 2023The p.E1556K variant (also known as c.4666G>A), located in coding exon 31 of the MYH6 gene, results from a G to A substitution at nucleotide position 4666. The glutamic acid at codon 1556 is replaced by lysine, an amino acid with similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.86
BayesDel_addAF
Uncertain
0.13
D
BayesDel_noAF
Pathogenic
0.27
CADD
Pathogenic
32
DANN
Pathogenic
1.0
DEOGEN2
Uncertain
0.65
D;D
Eigen
Pathogenic
0.70
Eigen_PC
Uncertain
0.65
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Uncertain
0.94
D;.
M_CAP
Uncertain
0.14
D
MetaRNN
Pathogenic
0.81
D;D
MetaSVM
Uncertain
0.45
D
MutationAssessor
Pathogenic
3.0
M;M
MutationTaster
Benign
1.0
D;D
PrimateAI
Pathogenic
0.85
D
PROVEAN
Uncertain
-2.6
D;D
REVEL
Pathogenic
0.81
Sift
Uncertain
0.0020
D;D
Sift4G
Benign
0.091
T;T
Polyphen
0.97
D;D
Vest4
0.86
MVP
0.93
MPC
0.81
ClinPred
0.29
T
GERP RS
4.3
Varity_R
0.50
gMVP
0.69

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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs148582147; hg19: chr14-23855817; API