14-23389018-C-T

Position:

chr14-23389018-C-T

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 1P and 5B. PP2BP4BS2

The NM_002471.4(MYH6):c.4016G>A(p.Arg1339Gln) variant causes a missense change. The variant allele was found at a frequency of 0.0000412 in 1,506,516 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.000075 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000038 ( 0 hom. )

Consequence

MYH6
NM_002471.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:4

Conservation

PhyloP100: 5.97

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]

MYH6 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -4 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.

BP4

Computational evidence support a benign effect (MetaRNN=0.41455308).

BS2

High AC in GnomAd4 at 11 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MYH6	NM_002471.4 linkuse as main transcript	c.4016G>A	p.Arg1339Gln	missense_variant	29/39	ENST00000405093.9	NP_002462.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MYH6	ENST00000405093.9 linkuse as main transcript	c.4016G>A	p.Arg1339Gln	missense_variant	29/39	5	NM_002471.4	ENSP00000386041	P1

Frequencies

GnomAD3 genomes

AF:

0.0000749

AC:

AN:

146924

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000219

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000684

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:

0.00

Gnomad OTH

AF:

0.000487

GnomAD3 exomes

AF:

0.0000481

AC:

AN:

249586

Hom.:

AF XY:

0.0000592

AC XY:

AN XY:

135064

show subpopulations

Gnomad AFR exome

AF:

0.0000619

Gnomad AMR exome

AF:

0.0000290

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000545

Gnomad SAS exome

AF:

0.0000654

Gnomad FIN exome

AF:

0.000141

Gnomad NFE exome

AF:

0.0000355

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000375

AC:

AN:

1359442

Hom.:

Cov.:

AF XY:

0.0000459

AC XY:

AN XY:

675094

show subpopulations

Gnomad4 AFR exome

AF:

0.000153

Gnomad4 AMR exome

AF:

0.000145

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000110

Gnomad4 SAS exome

AF:

0.000153

Gnomad4 FIN exome

AF:

0.0000954

Gnomad4 NFE exome

AF:

0.0000172

Gnomad4 OTH exome

AF:

0.0000184

GnomAD4 genome

AF:

0.0000748

AC:

AN:

147074

Hom.:

Cov.:

AF XY:

0.0000977

AC XY:

AN XY:

71652

show subpopulations

Gnomad4 AFR

AF:

0.000218

Gnomad4 AMR

AF:

0.0000683

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.000482

Alfa

AF:

0.0000331

Hom.:

Bravo

AF:

0.0000567

ExAC

AF:

0.0000165

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Hypertrophic cardiomyopathy 14

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

May 08, 2019

In 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. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C35"). This variant has not been reported in the literature in individuals with MYH6-related disease. ClinVar contains an entry for this variant (Variation ID:¬†239172). This variant is present in population databases (rs766238876, ExAC 0.006%). This sequence change replaces arginine with glutamine at codon 1339 of the MYH6 protein (p.Arg1339Gln). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and glutamine. -

Dilated cardiomyopathy 1EE;C2750467:Hypertrophic cardiomyopathy 14;C3279790:Atrial septal defect 3;C3279791:Sick sinus syndrome 3, susceptibility to;C3495498:Hypertrophic cardiomyopathy 1

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Jul 22, 2021

- -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

May 24, 2019

In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Has not been previously published as pathogenic or benign to our knowledge -

Cardiovascular phenotype

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 03, 2024

The p.R1339Q variant (also known as c.4016G>A), located in coding exon 27 of the MYH6 gene, results from a G to A substitution at nucleotide position 4016. The arginine at codon 1339 is replaced by glutamine, an amino acid with highly similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. 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

Benign

0.15

BayesDel_addAF

Uncertain

0.038

BayesDel_noAF

Uncertain

0.0

CADD

Uncertain

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.64

D;D

Eigen

Uncertain

0.29

Eigen_PC

Uncertain

0.37

FATHMM_MKL

Uncertain

0.97

LIST_S2

Uncertain

0.92

D;.

M_CAP

Benign

0.060

MetaRNN

Benign

0.41

T;T

MetaSVM

Uncertain

-0.11

MutationAssessor

Benign

1.8

L;L

MutationTaster

Benign

1.0

D;D

PrimateAI

Uncertain

0.78

PROVEAN

Uncertain

-2.6

D;D

REVEL

Uncertain

0.63

Sift

Benign

0.066

T;T

Sift4G

Benign

0.18

T;T

Polyphen

0.56

P;P

Vest4

0.54

MVP

0.91

MPC

0.43

ClinPred

0.56

GERP RS

4.7

Varity_R

0.21

gMVP

0.33

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over