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rs144329079

chr14-23384607-G-Achr14-23384607-G-C

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_ModerateBP6BP7BS1BS2

The NM_002471.4(MYH6):c.5400C>T(p.Asp1800=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000258 in 1,613,836 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0013 ( 1 hom., cov: 33)
Exomes 𝑓: 0.00015 ( 1 hom. )

Consequence

MYH6
NM_002471.4 synonymous

Scores

2

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:8

Conservation

PhyloP100: 0.346
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]

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -12 ACMG points.

BP4
?
    BP4 - Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc.)
Computational evidence support a benign effect (BayesDel_noAF=-0.46).
BP6
?
    BP6 - Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation
Variant 14-23384607-G-A is Benign according to our data. Variant chr14-23384607-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 44535.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Benign=3, Uncertain_significance=1}. Variant chr14-23384607-G-A is described in Lovd as [Likely_benign]. Variant chr14-23384607-G-A is described in Lovd as [Benign].
BP7
?
    BP7 - A synonymous (silent) variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved
Synonymous conserved (PhyloP=0.346 with no splicing effect.
BS1
?
    BS1 - Allele frequency is greater than expected for disorder
Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00128 (195/152362) while in subpopulation AFR AF= 0.00457 (190/41586). AF 95% confidence interval is 0.00404. There are 1 homozygotes in gnomad4. There are 95 alleles in male gnomad4 subpopulation. This position pass quality control queck.
BS2
?
    BS2 - Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age
High AC in GnomAd at 195 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
MYH6NM_002471.4 linkuse as main transcriptc.5400C>T p.Asp1800= synonymous_variant 36/39 ENST00000405093.9

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
MYH6ENST00000405093.9 linkuse as main transcriptc.5400C>T p.Asp1800= synonymous_variant 36/395 NM_002471.4 P1

Frequencies

GnomAD3 genomes
?
    Genome Aggregation Database, over 76,156 genomes
AF:
0.00128
AC:
195
AN:
152244
Hom.:
1
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.00458
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000131
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:
0.0000147
Gnomad OTH
AF:
0.000955
GnomAD3 exomes
AF:
0.000342
AC:
86
AN:
251462
Hom.:
0
AF XY:
0.000243
AC XY:
33
AN XY:
135914
show subpopulations
Gnomad AFR exome
AF:
0.00486
Gnomad AMR exome
AF:
0.000173
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00000879
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.000152
AC:
222
AN:
1461474
Hom.:
1
Cov.:
34
AF XY:
0.000125
AC XY:
91
AN XY:
727050
show subpopulations
Gnomad4 AFR exome
AF:
0.00592
Gnomad4 AMR exome
AF:
0.000201
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.0000252
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00
Gnomad4 OTH exome
AF:
0.000215
GnomAD4 genome
?
    Genome Aggregation Database, over 76,156 genomes
AF:
0.00128
AC:
195
AN:
152362
Hom.:
1
Cov.:
33
AF XY:
0.00128
AC XY:
95
AN XY:
74506
show subpopulations
Gnomad4 AFR
AF:
0.00457
Gnomad4 AMR
AF:
0.000131
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000147
Gnomad4 OTH
AF:
0.000945
Alfa
AF:
0.000469
Hom.:
0
Bravo
AF:
0.00151
Asia WGS
AF:
0.000577
AC:
2
AN:
3478
EpiCase
AF:
0.0000545
EpiControl
AF:
0.00

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:1Benign:8
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

not provided Uncertain:1Benign:4
Likely benign, no assertion criteria providedclinical testingGenome Diagnostics Laboratory, University Medical Center Utrecht-- -
Likely benign, no assertion criteria providedclinical testingClinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center-- -
Uncertain significance, criteria provided, single submitterclinical testingEurofins Ntd Llc (ga)Dec 16, 2014- -
Likely benign, criteria provided, single submitterclinical testingCeGaT Center for Human Genetics TuebingenJan 01, 2024MYH6: BP4, BP7 -
Likely benign, criteria provided, single submitterclinical testingGeneDxDec 15, 2020- -
not specified Benign:2
Benign, criteria provided, single submitterclinical testingLaboratory for Molecular Medicine, Mass General Brigham Personalized MedicineFeb 07, 2012Benign based on high population frequency (17/3755 chromosomes). -
Benign, no assertion criteria providedclinical testingClinical Genetics, Academic Medical Center-- -
Hypertrophic cardiomyopathy 14 Benign:1
Benign, criteria provided, single submitterclinical testingInvitaeNov 08, 2023- -
MYH6-related disorder Benign:1
Benign, criteria provided, single submitterclinical testingPreventionGenetics, part of Exact SciencesJun 07, 2019This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.46
Cadd
Benign
6.3
Dann
Benign
0.87

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: rs144329079; hg19: chr14-23853816; COSMIC: COSV100198211; COSMIC: COSV100198211; API