rs178637

Variant names:

• chr14-23385063-T-C
• rs178637
• NM_002471.4:c.5164-22A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_002471.4(MYH6):​c.5164-22A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0808 in 1,613,572 control chromosomes in the GnomAD database, including 5,824 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). There are indicators that this mutation may affect the branch point..

• Frequency:
  • Genomes: 𝑓 0.078 (526 hom., cov: 32)
  • Exomes 𝑓: 0.081 (5298 hom.)
• Consequence: MYH6 NM_002471.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.698

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

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: This position, referring to a specific DNA site, is a probable branch point but is likely benign (scored 1 / 10, using the threshold of <=3). The score ranges from 0 to 10, with values ≤3 considered benign and >5 classified as pathogenic. Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BP6: Variant 14-23385063-T-C is Benign according to our data. Variant chr14-23385063-T-C is described in ClinVar as [Benign]. Clinvar id is 258713.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-23385063-T-C is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0793 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYH6	NM_002471.4	c.5164-22A>G		intron_variant	Intron 34 of 38	ENST00000405093.9	NP_002462.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MYH6	ENST00000405093.9	c.5164-22A>G		intron_variant	Intron 34 of 38	5	NM_002471.4	ENSP00000386041.3

Frequencies

GnomAD3 genomes AF: 0.0779 AC: 11836 AN: 152016 Hom.: 528 Cov.: 32

Gnomad AFR AF: 0.0615

Gnomad AMI AF: 0.0143

Gnomad AMR AF: 0.0557

Gnomad ASJ AF: 0.0729

Gnomad EAS AF: 0.0637

Gnomad SAS AF: 0.0778

Gnomad FIN AF: 0.168

Gnomad MID AF: 0.0696

Gnomad NFE AF: 0.0811

Gnomad OTH AF: 0.0742

GnomAD2 exomes AF: 0.0793 AC: 19936 AN: 251448 AF XY: 0.0805

Gnomad AFR exome AF: 0.0636

Gnomad AMR exome AF: 0.0296

Gnomad ASJ exome AF: 0.0702

Gnomad EAS exome AF: 0.0624

Gnomad FIN exome AF: 0.167

Gnomad NFE exome AF: 0.0831

Gnomad OTH exome AF: 0.0776

GnomAD4 exome AF: 0.0811 AC: 118582 AN: 1461438 Hom.: 5298 Cov.: 34 AF XY: 0.0815 AC XY: 59254 AN XY: 727072

Gnomad4 AFR exome AF: 0.0609 AC: 2039 AN: 33470

Gnomad4 AMR exome AF: 0.0321 AC: 1436 AN: 44722

Gnomad4 ASJ exome AF: 0.0698 AC: 1825 AN: 26132

Gnomad4 EAS exome AF: 0.0850 AC: 3374 AN: 39690

Gnomad4 SAS exome AF: 0.0797 AC: 6877 AN: 86250

Gnomad4 FIN exome AF: 0.159 AC: 8495 AN: 53376

Gnomad4 NFE exome AF: 0.0805 AC: 89450 AN: 1111654

Gnomad4 Remaining exome AF: 0.0787 AC: 4751 AN: 60376

GnomAD4 genome AF: 0.0777 AC: 11824 AN: 152134 Hom.: 526 Cov.: 32 AF XY: 0.0810 AC XY: 6022 AN XY: 74368

Gnomad4 AFR AF: 0.0612 AC: 0.0612206 AN: 0.0612206

Gnomad4 AMR AF: 0.0555 AC: 0.0555119 AN: 0.0555119

Gnomad4 ASJ AF: 0.0729 AC: 0.0729107 AN: 0.0729107

Gnomad4 EAS AF: 0.0638 AC: 0.0638132 AN: 0.0638132

Gnomad4 SAS AF: 0.0771 AC: 0.0770825 AN: 0.0770825

Gnomad4 FIN AF: 0.168 AC: 0.168463 AN: 0.168463

Gnomad4 NFE AF: 0.0811 AC: 0.0810688 AN: 0.0810688

Gnomad4 OTH AF: 0.0729 AC: 0.0729167 AN: 0.0729167

Alfa AF: 0.0768 Hom.: 961

Bravo AF: 0.0683

Asia WGS AF: 0.0760 AC: 264 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	1.2
DANN	Benign	0.58
BranchPoint Hunter		1.0
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs178637; hg19: chr14-23854272; COSMIC: COSV62453249; COSMIC: COSV62453249;