rs529427223

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 1P and 5B. PP2BP6BS2

The NM_002471.4(MYH6):​c.245C>T​(p.Pro82Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000384 in 1,614,132 control chromosomes in the GnomAD database, including 1 homozygotes. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000040 ( 1 hom. )

Consequence

MYH6
NM_002471.4 missense

Scores

9
8
2

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:1

Conservation

PhyloP100: 7.97
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]

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.
BP6
Variant 14-23405727-G-A is Benign according to our data. Variant chr14-23405727-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 164256.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=2, Likely_benign=1}.
BS2
High AC in GnomAdExome4 at 59 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
MYH6NM_002471.4 linkuse as main transcriptc.245C>T p.Pro82Leu missense_variant 4/39 ENST00000405093.9 NP_002462.2

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
MYH6ENST00000405093.9 linkuse as main transcriptc.245C>T p.Pro82Leu missense_variant 4/395 NM_002471.4 ENSP00000386041 P1
MYH6ENST00000557461.2 linkuse as main transcriptn.312C>T non_coding_transcript_exon_variant 4/145

Frequencies

GnomAD3 genomes
AF:
0.0000197
AC:
3
AN:
152120
Hom.:
0
Cov.:
32
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:
0.00
Gnomad SAS
AF:
0.000622
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.000111
AC:
28
AN:
251490
Hom.:
0
AF XY:
0.000132
AC XY:
18
AN XY:
135920
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.000849
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00000879
Gnomad OTH exome
AF:
0.000163
GnomAD4 exome
AF:
0.0000404
AC:
59
AN:
1461894
Hom.:
1
Cov.:
33
AF XY:
0.0000523
AC XY:
38
AN XY:
727248
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.000533
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000360
Gnomad4 OTH exome
AF:
0.000149
GnomAD4 genome
AF:
0.0000197
AC:
3
AN:
152238
Hom.:
0
Cov.:
32
AF XY:
0.0000134
AC XY:
1
AN XY:
74434
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.000623
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.00
ExAC
AF:
0.000115
AC:
14
Asia WGS
AF:
0.000866
AC:
3
AN:
3478

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:2Benign:1
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

not specified Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingLaboratory for Molecular Medicine, Mass General Brigham Personalized MedicineAug 21, 2014The Pro82Leu variant in MYH6 gene has not been previously reported in individual s with cardiomyopathy or in large population studies. Computational prediction t ools and conservation analysis suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, the clinical significance of the Pro82Leu variant is uncertain. -
Cardiovascular phenotype Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsMar 06, 2020The p.P82L variant (also known as c.245C>T), located in coding exon 2 of the MYH6 gene, results from a C to T substitution at nucleotide position 245. The proline at codon 82 is replaced by leucine, an amino acid with similar properties. This alteration has been reported in a hypertrophic cardiomyopathy (HCM) cohort; however, clinical details were limited (Lopes LR et al. Heart, 2015 Feb;101:294-301). 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. -
Hypertrophic cardiomyopathy 14 Benign:1
Likely benign, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJan 04, 2024- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.91
BayesDel_addAF
Benign
-0.095
T
BayesDel_noAF
Uncertain
0.010
CADD
Pathogenic
31
DANN
Uncertain
1.0
DEOGEN2
Uncertain
0.75
D;D
Eigen
Pathogenic
0.86
Eigen_PC
Pathogenic
0.76
FATHMM_MKL
Pathogenic
1.0
D
LIST_S2
Uncertain
0.91
D;.
M_CAP
Uncertain
0.18
D
MetaRNN
Uncertain
0.70
D;D
MetaSVM
Uncertain
0.40
D
MutationAssessor
Pathogenic
3.9
H;H
MutationTaster
Benign
1.0
D;D
PrimateAI
Uncertain
0.78
T
PROVEAN
Pathogenic
-7.5
D;D
REVEL
Pathogenic
0.72
Sift
Pathogenic
0.0
D;D
Sift4G
Pathogenic
0.0010
D;D
Polyphen
1.0
D;D
Vest4
0.81
MutPred
0.47
Loss of disorder (P = 0.019);Loss of disorder (P = 0.019);
MVP
0.85
MPC
1.1
ClinPred
0.99
D
GERP RS
3.9
Varity_R
0.64
gMVP
0.70

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: rs529427223; hg19: chr14-23874936; COSMIC: COSV62448502; API