rs452036

Positions:

• chr14-23396676-G-A
• chr14-23396676-G-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_002471.4(MYH6):​c.2292+18C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.356 in 1,613,750 control chromosomes in the GnomAD database, including 107,860 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.42 (14545 hom., cov: 33)
  • Exomes 𝑓: 0.35 (93315 hom.)
• Consequence: MYH6 NM_002471.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -1.65

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.96).
• BP6: Variant 14-23396676-G-A is Benign according to our data. Variant chr14-23396676-G-A is described in ClinVar as [Benign]. Clinvar id is 258709.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-23396676-G-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.618 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MYH6	NM_002471.4	c.2292+18C>T		intron_variant		ENST00000405093.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYH6	ENST00000405093.9	c.2292+18C>T		intron_variant		5	NM_002471.4	P1

Frequencies

GnomAD3 genomes AF: 0.415 AC: 63087 AN: 152036 Hom.: 14498 Cov.: 33

Gnomad AFR AF: 0.624

Gnomad AMI AF: 0.298

Gnomad AMR AF: 0.316

Gnomad ASJ AF: 0.454

Gnomad EAS AF: 0.162

Gnomad SAS AF: 0.295

Gnomad FIN AF: 0.268

Gnomad MID AF: 0.399

Gnomad NFE AF: 0.360

Gnomad OTH AF: 0.416

GnomAD3 exomes AF: 0.328 AC: 82470 AN: 251054 Hom.: 15041 AF XY: 0.328 AC XY: 44492 AN XY: 135680

Gnomad AFR exome AF: 0.620

Gnomad AMR exome AF: 0.226

Gnomad ASJ exome AF: 0.447

Gnomad EAS exome AF: 0.163

Gnomad SAS exome AF: 0.300

Gnomad FIN exome AF: 0.264

Gnomad NFE exome AF: 0.353

Gnomad OTH exome AF: 0.351

GnomAD4 exome AF: 0.350 AC: 511550 AN: 1461596 Hom.: 93315 Cov.: 53 AF XY: 0.348 AC XY: 253247 AN XY: 727110

Gnomad4 AFR exome AF: 0.634

Gnomad4 AMR exome AF: 0.237

Gnomad4 ASJ exome AF: 0.455

Gnomad4 EAS exome AF: 0.147

Gnomad4 SAS exome AF: 0.300

Gnomad4 FIN exome AF: 0.270

Gnomad4 NFE exome AF: 0.357

Gnomad4 OTH exome AF: 0.365

GnomAD4 genome AF: 0.415 AC: 63187 AN: 152154 Hom.: 14545 Cov.: 33 AF XY: 0.408 AC XY: 30361 AN XY: 74406

Gnomad4 AFR AF: 0.624

Gnomad4 AMR AF: 0.316

Gnomad4 ASJ AF: 0.454

Gnomad4 EAS AF: 0.162

Gnomad4 SAS AF: 0.295

Gnomad4 FIN AF: 0.268

Gnomad4 NFE AF: 0.360

Gnomad4 OTH AF: 0.425

Alfa AF: 0.352 Hom.: 11891

Bravo AF: 0.425

Asia WGS AF: 0.283 AC: 985 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:5

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

Hypertrophic cardiomyopathy 14 Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Mar 03, 2015

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.96
CADD	Benign	0.0020
DANN	Benign	0.15

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: rs452036; hg19: chr14-23865885; COSMIC: COSV62449823; COSMIC: COSV62449823;