14-23390401-C-T

Position:

chr14-23390401-C-T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2BP4_StrongBP6_Very_StrongBA1

The NM_002471.4(MYH6):c.3388G>A(p.Ala1130Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.114 in 1,609,018 control chromosomes in the GnomAD database, including 7,777 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.089 ( 591 hom., cov: 31)

Exomes 𝑓: 0.12 ( 7186 hom. )

Consequence

MYH6
NM_002471.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:12

Conservation

PhyloP100: 0.899

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 Benign. Variant got -19 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=0.0033628345).

BP6

Variant 14-23390401-C-T is Benign according to our data. Variant chr14-23390401-C-T is described in ClinVar as [Benign]. Clinvar id is 44483.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-23390401-C-T is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.121 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MYH6	NM_002471.4 linkuse as main transcript	c.3388G>A	p.Ala1130Thr	missense_variant	26/39	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.3388G>A	p.Ala1130Thr	missense_variant	26/39	5	NM_002471.4	ENSP00000386041	P1

Frequencies

GnomAD3 genomes

AF:

0.0887

AC:

13458

AN:

151666

Hom.:

588

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0260

Gnomad AMI

AF:

0.0692

Gnomad AMR

AF:

0.109

Gnomad ASJ

AF:

0.0952

Gnomad EAS

AF:

0.0714

Gnomad SAS

AF:

0.0686

Gnomad FIN

AF:

0.0916

Gnomad MID

AF:

0.136

Gnomad NFE

AF:

0.124

Gnomad OTH

AF:

0.113

GnomAD3 exomes

AF:

0.0947

AC:

23065

AN:

243682

Hom.:

827

AF XY:

0.0958

AC XY:

12710

AN XY:

132668

show subpopulations

Gnomad AFR exome

AF:

0.0216

Gnomad AMR exome

AF:

0.0950

Gnomad ASJ exome

AF:

0.0879

Gnomad EAS exome

AF:

0.0671

Gnomad SAS exome

AF:

0.0664

Gnomad FIN exome

AF:

0.0819

Gnomad NFE exome

AF:

0.119

Gnomad OTH exome

AF:

0.109

GnomAD4 exome

AF:

0.117

AC:

170393

AN:

1457236

Hom.:

7186

Cov.:

AF XY:

0.115

AC XY:

83702

AN XY:

724798

show subpopulations

Gnomad4 AFR exome

AF:

0.0221

Gnomad4 AMR exome

AF:

0.0976

Gnomad4 ASJ exome

AF:

0.0937

Gnomad4 EAS exome

AF:

0.0752

Gnomad4 SAS exome

AF:

0.0668

Gnomad4 FIN exome

AF:

0.0806

Gnomad4 NFE exome

AF:

0.129

Gnomad4 OTH exome

AF:

0.100

GnomAD4 genome

AF:

0.0887

AC:

13467

AN:

151782

Hom.:

591

Cov.:

AF XY:

0.0861

AC XY:

6389

AN XY:

74212

show subpopulations

Gnomad4 AFR

AF:

0.0259

Gnomad4 AMR

AF:

0.109

Gnomad4 ASJ

AF:

0.0952

Gnomad4 EAS

AF:

0.0712

Gnomad4 SAS

AF:

0.0695

Gnomad4 FIN

AF:

0.0916

Gnomad4 NFE

AF:

0.124

Gnomad4 OTH

AF:

0.119

Alfa

AF:

0.109

Hom.:

210

Bravo

AF:

0.0906

TwinsUK

AF:

0.138

AC:

513

ALSPAC

AF:

0.129

AC:

499

ExAC

AF:

0.0910

AC:

11012

Asia WGS

AF:

0.0760

AC:

263

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:12

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:6

Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Sep 30, 2011	Benign based on high population frequency (rs28730771) -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	research	Biesecker Lab/Clinical Genomics Section, National Institutes of Health	Jun 24, 2013	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

not provided

Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 29, 2023	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Hypertrophic cardiomyopathy 14

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

Cardiomyopathy

Benign:1

Benign, criteria provided, single submitter

clinical testing

CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario

Nov 16, 2015

- -

Cardiovascular phenotype

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 15, 2015

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.45

BayesDel_noAF

Benign

-0.30

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.44

T;T

Eigen

Benign

0.12

Eigen_PC

Benign

0.050

FATHMM_MKL

Benign

0.64

LIST_S2

Benign

0.46

T;.

MetaRNN

Benign

0.0034

T;T

MetaSVM

Benign

-0.88

MutationAssessor

Benign

2.0

M;M

MutationTaster

Benign

0.0038

P;P

PrimateAI

Uncertain

0.62

PROVEAN

Benign

-1.4

N;N

REVEL

Uncertain

0.40

Sift

Benign

0.33

T;T

Sift4G

Benign

0.12

T;T

Polyphen

0.89

P;P

Vest4

0.47

MPC

2.8

ClinPred

0.037

GERP RS

3.4

Varity_R

0.033

gMVP

0.52

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.

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