rs770492637

chr14-23389057-T-TG

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_Strong BS1 BS2

The NM_002471.4(MYH6):c.3979-3_3979-2insC variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000288 in 981,312 control chromosomes in the GnomAD database, including 3 homozygotes. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0017 (1 hom., cov: 31)
  • Exomes 𝑓: 0.00015 (2 hom.)
• Consequence: MYH6 NM_002471.4 splice_region, splice_polypyrimidine_tract, intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 3.08

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 -16 ACMG points.

• BP6: Variant 14-23389057-T-TG is Benign according to our data. Variant chr14-23389057-T-TG is described in ClinVar as [Likely_benign]. Clinvar id is 414316.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00174 (151/86986) while in subpopulation AFR AF= 0.00868 (141/16250). AF 95% confidence interval is 0.00751. There are 1 homozygotes in gnomad4. There are 84 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High AC in GnomAd at 149 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MYH6	NM_002471.4	c.3979-3_3979-2insC		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000405093.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYH6	ENST00000405093.9	c.3979-3_3979-2insC		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		5	NM_002471.4	P1

Frequencies

GnomAD3 genomes AF: 0.00171 AC: 149 AN: 86938 Hom.: 1 Cov.: 31

Gnomad AFR AF: 0.00857

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000582

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000405

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000677

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.000148 AC: 132 AN: 894326 Hom.: 2 Cov.: 48 AF XY: 0.000111 AC XY: 50 AN XY: 449026

Gnomad4 AFR exome AF: 0.00358

Gnomad4 AMR exome AF: 0.000226

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000367

Gnomad4 SAS exome AF: 0.0000847

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000456

Gnomad4 OTH exome AF: 0.000361

GnomAD4 genome AF: 0.00174 AC: 151 AN: 86986 Hom.: 1 Cov.: 31 AF XY: 0.00196 AC XY: 84 AN XY: 42840

Gnomad4 AFR AF: 0.00868

Gnomad4 AMR AF: 0.000581

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000404

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000677

Gnomad4 OTH AF: 0.00

Alfa AF: 0.00101 Hom.: 0

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

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

May 07, 2022

- -

Hypertrophic cardiomyopathy 14 Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

Dilated cardiomyopathy 1EE;C2750467:Hypertrophic cardiomyopathy 14;C3279790:Atrial septal defect 3;C3279791:Sick sinus syndrome 3, susceptibility to;C3495498:Hypertrophic cardiomyopathy 1 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 09, 2021

- -

MYH6-related condition Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 29, 2019

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Cardiovascular phenotype Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 04, 2019

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

Splicing

Name	Calibrated prediction	Score	Prediction
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: rs770492637; hg19: chr14-23858266;