rs193922653

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_002471.4(MYH6):c.4651-12A>C variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00395 in 144,334 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.0039 ( 1 hom., cov: 31)

Exomes 𝑓: 0.00057 ( 1 hom. )

Failed GnomAD Quality Control

Consequence

MYH6
NM_002471.4 splice_polypyrimidine_tract, intron

Scores

Splicing: ADA: 0.000007133

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:9

Conservation

PhyloP100: -0.865

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 -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.95).

BP6

Variant 14-23386635-T-G is Benign according to our data. Variant chr14-23386635-T-G is described in ClinVar as [Benign]. Clinvar id is 36630.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-23386635-T-G is described in Lovd as [Benign]. Variant chr14-23386635-T-G is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00395 (570/144334) while in subpopulation AFR AF= 0.0136 (539/39752). AF 95% confidence interval is 0.0126. There are 1 homozygotes in gnomad4. There are 246 alleles in male gnomad4 subpopulation. This position pass quality control queck.

BS2

High AC in GnomAd at 571 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MYH6	NM_002471.4 linkuse as main transcript	c.4651-12A>C		splice_polypyrimidine_tract_variant, intron_variant		ENST00000405093.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYH6	ENST00000405093.9 linkuse as main transcript	c.4651-12A>C		splice_polypyrimidine_tract_variant, intron_variant		5	NM_002471.4	P1

Frequencies

GnomAD3 genomes

AF:

0.00396

AC:

571

AN:

144192

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0136

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00123

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000501

Gnomad FIN

AF:

0.000221

Gnomad MID

AF:

0.00325

Gnomad NFE

AF:

0.0000456

Gnomad OTH

AF:

0.00247

GnomAD3 exomes

AF:

0.00100

AC:

244

AN:

243406

Hom.:

AF XY:

0.000700

AC XY:

AN XY:

131338

show subpopulations

Gnomad AFR exome

AF:

0.0137

Gnomad AMR exome

AF:

0.000641

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:

0.00000913

Gnomad OTH exome

AF:

0.000503

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.000567

AC:

604

AN:

1066134

Hom.:

Cov.:

AF XY:

0.000480

AC XY:

258

AN XY:

537670

show subpopulations

Gnomad4 AFR exome

AF:

0.0163

Gnomad4 AMR exome

AF:

0.000751

Gnomad4 ASJ exome

AF:

0.000471

Gnomad4 EAS exome

AF:

0.000157

Gnomad4 SAS exome

AF:

0.0000386

Gnomad4 FIN exome

AF:

0.000105

Gnomad4 NFE exome

AF:

0.000112

Gnomad4 OTH exome

AF:

0.00107

GnomAD4 genome

AF:

0.00395

AC:

570

AN:

144334

Hom.:

Cov.:

AF XY:

0.00350

AC XY:

246

AN XY:

70228

show subpopulations

Gnomad4 AFR

AF:

0.0136

Gnomad4 AMR

AF:

0.00123

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000500

Gnomad4 FIN

AF:

0.000221

Gnomad4 NFE

AF:

0.0000456

Gnomad4 OTH

AF:

0.00244

Alfa

AF:

0.00225

Hom.:

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:5

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jun 25, 2015	c.4651-12A>C in intron 32 of MYH6: This variant is not expected to have clinical significance because it has been identified in 1.4% (139/10018) of African chro mosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.or g/, dbSNP rs193922653). -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
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	GeneDx	Jan 12, 2017	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -

Hypertrophic cardiomyopathy 14

Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

Cardiomyopathy

Benign:1

Benign, no assertion criteria provided

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

May 26, 2015

- -

not provided

Benign:1

Likely benign, no assertion criteria provided

clinical testing

Genome Diagnostics Laboratory, University Medical Center Utrecht

- -

Primary dilated cardiomyopathy

Benign:1

Benign, criteria provided, single submitter

clinical testing

Center for Advanced Laboratory Medicine, UC San Diego Health, University of California San Diego

May 08, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.95

Cadd

Benign

1.7

Dann

Benign

0.40

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.0000071

dbscSNV1_RF

Benign

0.0

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