chr14-23387687-A-G

Variant names:

• chr14-23387687-A-G
• rs178642
• NM_002471.4:c.4526-34T>C

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.4526-34T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.488 in 1,613,696 control chromosomes in the GnomAD database, including 194,778 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.48 (17614 hom., cov: 31)
  • Exomes 𝑓: 0.49 (177164 hom.)
• Consequence: MYH6 NM_002471.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.242
• Publications: 16 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=-0.77).
• BP6: Variant 14-23387687-A-G is Benign according to our data. Variant chr14-23387687-A-G is described in ClinVar as Benign. ClinVar VariationId is 258710.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.611 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYH6	NM_002471.4	c.4526-34T>C		intron_variant	Intron 31 of 38	ENST00000405093.9	NP_002462.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MYH6	ENST00000405093.9	c.4526-34T>C		intron_variant	Intron 31 of 38	5	NM_002471.4	ENSP00000386041.3

Frequencies

GnomAD3 genomes AF: 0.479 AC: 72653 AN: 151720 Hom.: 17595 Cov.: 31

Gnomad AFR AF: 0.418

Gnomad AMI AF: 0.367

Gnomad AMR AF: 0.500

Gnomad ASJ AF: 0.516

Gnomad EAS AF: 0.630

Gnomad SAS AF: 0.396

Gnomad FIN AF: 0.583

Gnomad MID AF: 0.424

Gnomad NFE AF: 0.490

Gnomad OTH AF: 0.450

GnomAD2 exomes AF: 0.500 AC: 125823 AN: 251412 AF XY: 0.492

Gnomad AFR exome AF: 0.413

Gnomad AMR exome AF: 0.553

Gnomad ASJ exome AF: 0.536

Gnomad EAS exome AF: 0.621

Gnomad FIN exome AF: 0.575

Gnomad NFE exome AF: 0.490

Gnomad OTH exome AF: 0.497

GnomAD4 exome AF: 0.489 AC: 715226 AN: 1461858 Hom.: 177164 Cov.: 70 AF XY: 0.487 AC XY: 353879 AN XY: 727228

African (AFR) AF: 0.414 AC: 13845 AN: 33480

American (AMR) AF: 0.553 AC: 24712 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.531 AC: 13877 AN: 26134

East Asian (EAS) AF: 0.647 AC: 25686 AN: 39700

South Asian (SAS) AF: 0.390 AC: 33637 AN: 86258

European-Finnish (FIN) AF: 0.566 AC: 30215 AN: 53414

Middle Eastern (MID) AF: 0.476 AC: 2747 AN: 5768

European-Non Finnish (NFE) AF: 0.486 AC: 540878 AN: 1111992

Other (OTH) AF: 0.491 AC: 29629 AN: 60396

GnomAD4 genome AF: 0.479 AC: 72707 AN: 151838 Hom.: 17614 Cov.: 31 AF XY: 0.485 AC XY: 35957 AN XY: 74182

African (AFR) AF: 0.418 AC: 17303 AN: 41410

American (AMR) AF: 0.501 AC: 7645 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.516 AC: 1791 AN: 3470

East Asian (EAS) AF: 0.630 AC: 3237 AN: 5142

South Asian (SAS) AF: 0.396 AC: 1908 AN: 4814

European-Finnish (FIN) AF: 0.583 AC: 6145 AN: 10532

Middle Eastern (MID) AF: 0.435 AC: 128 AN: 294

European-Non Finnish (NFE) AF: 0.490 AC: 33284 AN: 67898

Other (OTH) AF: 0.444 AC: 934 AN: 2104

Alfa AF: 0.485 Hom.: 25024

Bravo AF: 0.474

Asia WGS AF: 0.461 AC: 1600 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	-0.77
CADD	Benign	1.9
DANN	Benign	0.83
PhyloP100		0.24
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: rs178642; hg19: chr14-23856896; COSMIC: COSV62448750; COSMIC: COSV62448750;