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
• Publications: 12 publications found

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 Gene-Disease associations (from GenCC):

• hypertrophic cardiomyopathy 14

  Inheritance: AD Classification: STRONG, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), PanelApp Australia, Laboratory for Molecular Medicine
• Keppen-Lubinsky syndrome

  Inheritance: AD Classification: MODERATE Submitted by: Illumina
• familial isolated dilated cardiomyopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• atrial septal defect 3

  Inheritance: AD Classification: LIMITED Submitted by: G2P
• dilated cardiomyopathy

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen
• hypertrophic cardiomyopathy

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen

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 VariationId is 258713.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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

African (AFR) AF: 0.0609 AC: 2039 AN: 33470

American (AMR) AF: 0.0321 AC: 1436 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.0698 AC: 1825 AN: 26132

East Asian (EAS) AF: 0.0850 AC: 3374 AN: 39690

South Asian (SAS) AF: 0.0797 AC: 6877 AN: 86250

European-Finnish (FIN) AF: 0.159 AC: 8495 AN: 53376

Middle Eastern (MID) AF: 0.0581 AC: 335 AN: 5768

European-Non Finnish (NFE) AF: 0.0805 AC: 89450 AN: 1111654

Other (OTH) 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

African (AFR) AF: 0.0612 AC: 2542 AN: 41522

American (AMR) AF: 0.0555 AC: 848 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.0729 AC: 253 AN: 3470

East Asian (EAS) AF: 0.0638 AC: 328 AN: 5140

South Asian (SAS) AF: 0.0771 AC: 372 AN: 4826

European-Finnish (FIN) AF: 0.168 AC: 1782 AN: 10578

Middle Eastern (MID) AF: 0.0646 AC: 19 AN: 294

European-Non Finnish (NFE) AF: 0.0811 AC: 5513 AN: 68004

Other (OTH) AF: 0.0729 AC: 154 AN: 2112

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
PhyloP100		-0.70
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

Other links and lift over

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