14-23389062-A-G

Position:

• chr14-23389062-A-G

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BP6_Very_Strong

The NM_002471.4(MYH6):​c.3979-7T>C variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.015 (7 hom., cov: 26)
  • Exomes 𝑓: 0.016 (5 hom.)
  • Failed GnomAD Quality Control
• Consequence: MYH6 NM_002471.4 splice_region, intron
• Scores: Splicing: ADA: 0.00006140
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -0.588

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]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.75).
• BP6: Variant 14-23389062-A-G is Benign according to our data. Variant chr14-23389062-A-G is described in ClinVar as [Benign]. Clinvar id is 239170.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-23389062-A-G is described in Lovd as [Benign]. Variant chr14-23389062-A-G is described in Lovd as [Likely_benign].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MYH6	NM_002471.4	c.3979-7T>C		splice_region_variant, intron_variant		ENST00000405093.9	NP_002462.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MYH6	ENST00000405093.9	c.3979-7T>C		splice_region_variant, intron_variant		5	NM_002471.4	ENSP00000386041.3

Frequencies

GnomAD3 genomes AF: 0.00 AC: 1752 AN: 115424 Hom.: 7 Cov.: 26 FAILED QC

Gnomad AFR AF: 0.0155

Gnomad AMI AF: 0.0133

Gnomad AMR AF: 0.0103

Gnomad ASJ AF: 0.0120

Gnomad EAS AF: 0.0145

Gnomad SAS AF: 0.00992

Gnomad FIN AF: 0.0148

Gnomad MID AF: 0.00775

Gnomad NFE AF: 0.0168

Gnomad OTH AF: 0.0140

GnomAD3 exomes AF: 0.0589 AC: 8229 AN: 139674 Hom.: 2 AF XY: 0.0582 AC XY: 4436 AN XY: 76278

Gnomad AFR exome AF: 0.0175

Gnomad AMR exome AF: 0.0803

Gnomad ASJ exome AF: 0.0509

Gnomad EAS exome AF: 0.0708

Gnomad SAS exome AF: 0.0353

Gnomad FIN exome AF: 0.0594

Gnomad NFE exome AF: 0.0668

Gnomad OTH exome AF: 0.0588

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0162 AC: 17102 AN: 1053674 Hom.: 5 Cov.: 27 AF XY: 0.0180 AC XY: 9439 AN XY: 524690

Gnomad4 AFR exome AF: 0.0164

Gnomad4 AMR exome AF: 0.0685

Gnomad4 ASJ exome AF: 0.0221

Gnomad4 EAS exome AF: 0.0209

Gnomad4 SAS exome AF: 0.0465

Gnomad4 FIN exome AF: 0.0434

Gnomad4 NFE exome AF: 0.0103

Gnomad4 OTH exome AF: 0.0177

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.0152 AC: 1751 AN: 115534 Hom.: 7 Cov.: 26 AF XY: 0.0135 AC XY: 767 AN XY: 56790

Gnomad4 AFR AF: 0.0155

Gnomad4 AMR AF: 0.0103

Gnomad4 ASJ AF: 0.0120

Gnomad4 EAS AF: 0.0145

Gnomad4 SAS AF: 0.00992

Gnomad4 FIN AF: 0.0148

Gnomad4 NFE AF: 0.0168

Gnomad4 OTH AF: 0.0138

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 08, 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. -

not provided Benign:2

Likely benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jun 20, 2016	Variant summary: The MYH6 c.3979-7T>C variant involves the alteration of a non-conserved intronic nucleotide. One in silico tool predicts a benign outcome for this variant. 5/5 splice prediction tools predict no significant impact on normal splicing and ESEfinder predicts changes of binding motifs for RNA splicing enhancers. This variant was found in 267/76776 control chromosomes (2 homozygotes), predominantly observed in the African subpopulation at a frequency of 0.0154313 (122/7906). This frequency is about 617 times the estimated maximal expected allele frequency of a pathogenic MYH6 variant (0.000025), suggesting this is likely a benign polymorphism found primarily in the populations of African origin. The variant of interest has not, to our knowledge, been reported in affected individuals via publications or clinical diagnostic laboratories; nor evaluated for functional impact by in vivo/vitro studies. Taken together, this variant is classified as benign. -

Hypertrophic cardiomyopathy 14 Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 23, 2024

- -

Cardiomyopathy Benign:1

Benign, criteria provided, single submitter

clinical testing

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

Dec 12, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.75
CADD	Benign	2.5
DANN	Benign	0.76

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000061
dbscSNV1_RF	Benign	0.0020
SpliceAI score (max)		0.020		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

Other links and lift over

dbSNP: rs535111647; hg19: chr14-23858271;