14-23396780-G-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_ModerateBP6_Very_StrongBS2

The NM_002471.4(MYH6):​c.2206C>A​(p.Gln736Lys) variant causes a missense change. The variant allele was found at a frequency of 0.0000161 in 1,613,970 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 Likely benign (★★).

Frequency

Genomes: 𝑓 0.000033 ( 0 hom., cov: 33)
Exomes 𝑓: 0.000014 ( 0 hom. )

Consequence

MYH6
NM_002471.4 missense

Scores

10
9

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: 6.49
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 Benign. Variant got -14 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.19800502).
BP6
Variant 14-23396780-G-T is Benign according to our data. Variant chr14-23396780-G-T is described in ClinVar as [Likely_benign]. Clinvar id is 192123.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
BS2
High AC in GnomAd4 at 5 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
MYH6NM_002471.4 linkc.2206C>A p.Gln736Lys missense_variant Exon 19 of 39 ENST00000405093.9 NP_002462.2

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
MYH6ENST00000405093.9 linkc.2206C>A p.Gln736Lys missense_variant Exon 19 of 39 5 NM_002471.4 ENSP00000386041.3 P13533

Frequencies

GnomAD3 genomes
AF:
0.0000329
AC:
5
AN:
152180
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.000962
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000677
AC:
17
AN:
251166
Hom.:
0
AF XY:
0.0000516
AC XY:
7
AN XY:
135744
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.000924
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000144
AC:
21
AN:
1461672
Hom.:
0
Cov.:
35
AF XY:
0.0000124
AC XY:
9
AN XY:
727146
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.000428
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000270
Gnomad4 OTH exome
AF:
0.0000166
GnomAD4 genome
AF:
0.0000328
AC:
5
AN:
152298
Hom.:
0
Cov.:
33
AF XY:
0.0000671
AC XY:
5
AN XY:
74462
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.000965
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.0000491
ExAC
AF:
0.0000576
AC:
7

ClinVar

Significance: Likely benign
Submissions summary: Benign:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Hypertrophic cardiomyopathy 14 Benign:1
Dec 17, 2024
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

not provided Benign:1
Jun 24, 2013
Biesecker Lab/Clinical Genomics Section, National Institutes of Health
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: research

- -

Cardiovascular phenotype Benign:1
Apr 12, 2024
Ambry Genetics
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This alteration is classified as likely 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
0.16
BayesDel_addAF
Benign
-0.12
T
BayesDel_noAF
Uncertain
-0.010
CADD
Uncertain
25
DANN
Uncertain
0.99
DEOGEN2
Uncertain
0.59
D;D
Eigen
Uncertain
0.48
Eigen_PC
Uncertain
0.48
FATHMM_MKL
Uncertain
0.97
D
LIST_S2
Uncertain
0.87
D;.
M_CAP
Benign
0.069
D
MetaRNN
Benign
0.20
T;T
MetaSVM
Uncertain
0.21
D
MutationAssessor
Benign
0.64
N;N
PrimateAI
Uncertain
0.71
T
PROVEAN
Benign
-2.1
N;N
REVEL
Uncertain
0.57
Sift
Benign
0.19
T;T
Sift4G
Benign
0.61
T;T
Polyphen
1.0
D;D
Vest4
0.38
MVP
0.93
MPC
1.3
ClinPred
0.21
T
GERP RS
4.5
Varity_R
0.24
gMVP
0.75

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: rs201411075; hg19: chr14-23865989; API