rs8006357

Variant names:

• chr14-23384420-T-C
• rs8006357
• NM_002471.4:c.5565+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.5565+22A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.257 in 1,607,124 control chromosomes in the GnomAD database, including 55,132 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.23 (4298 hom., cov: 32)
  • Exomes 𝑓: 0.26 (50834 hom.)
• Consequence: MYH6 NM_002471.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.558
• Publications: 13 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: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BP6: Variant 14-23384420-T-C is Benign according to our data. Variant chr14-23384420-T-C is described in ClinVar as Benign. ClinVar VariationId is 258714.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.346 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYH6	NM_002471.4	c.5565+22A>G		intron_variant	Intron 36 of 38	ENST00000405093.9	NP_002462.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MYH6	ENST00000405093.9	c.5565+22A>G		intron_variant	Intron 36 of 38	5	NM_002471.4	ENSP00000386041.3

Frequencies

GnomAD3 genomes AF: 0.231 AC: 35190 AN: 152028 Hom.: 4291 Cov.: 32

Gnomad AFR AF: 0.167

Gnomad AMI AF: 0.357

Gnomad AMR AF: 0.242

Gnomad ASJ AF: 0.342

Gnomad EAS AF: 0.189

Gnomad SAS AF: 0.359

Gnomad FIN AF: 0.217

Gnomad MID AF: 0.347

Gnomad NFE AF: 0.256

Gnomad OTH AF: 0.272

GnomAD2 exomes AF: 0.250 AC: 61649 AN: 246722 AF XY: 0.262

Gnomad AFR exome AF: 0.167

Gnomad AMR exome AF: 0.174

Gnomad ASJ exome AF: 0.326

Gnomad EAS exome AF: 0.189

Gnomad FIN exome AF: 0.212

Gnomad NFE exome AF: 0.264

Gnomad OTH exome AF: 0.269

GnomAD4 exome AF: 0.260 AC: 378545 AN: 1454978 Hom.: 50834 Cov.: 48 AF XY: 0.264 AC XY: 191093 AN XY: 724158

African (AFR) AF: 0.166 AC: 5557 AN: 33468

American (AMR) AF: 0.181 AC: 8088 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.327 AC: 8535 AN: 26134

East Asian (EAS) AF: 0.191 AC: 7570 AN: 39700

South Asian (SAS) AF: 0.358 AC: 30860 AN: 86230

European-Finnish (FIN) AF: 0.215 AC: 10130 AN: 47096

Middle Eastern (MID) AF: 0.331 AC: 1782 AN: 5386

European-Non Finnish (NFE) AF: 0.261 AC: 290742 AN: 1111956

Other (OTH) AF: 0.253 AC: 15281 AN: 60286

GnomAD4 genome AF: 0.232 AC: 35223 AN: 152146 Hom.: 4298 Cov.: 32 AF XY: 0.231 AC XY: 17219 AN XY: 74394

African (AFR) AF: 0.167 AC: 6933 AN: 41514

American (AMR) AF: 0.242 AC: 3701 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.342 AC: 1186 AN: 3472

East Asian (EAS) AF: 0.190 AC: 981 AN: 5160

South Asian (SAS) AF: 0.360 AC: 1736 AN: 4824

European-Finnish (FIN) AF: 0.217 AC: 2296 AN: 10590

Middle Eastern (MID) AF: 0.332 AC: 97 AN: 292

European-Non Finnish (NFE) AF: 0.256 AC: 17384 AN: 67976

Other (OTH) AF: 0.277 AC: 584 AN: 2112

Alfa AF: 0.253 Hom.: 17450

Bravo AF: 0.228

Asia WGS AF: 0.264 AC: 921 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	-0.89
CADD	Benign	1.4
DANN	Benign	0.51
PhyloP100		-0.56
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: rs8006357; hg19: chr14-23853629; COSMIC: COSV59306407; COSMIC: COSV59306407;