rs452036

Variant names:

• chr14-23396676-G-A
• rs452036
• NM_002471.4:c.2292+18C>T

Your query was ambiguous. Multiple possible variants found:

• chr14-23396676-G-A
• chr14-23396676-G-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.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:8
• Conservation: PhyloP100: -1.65
• Publications: 39 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=-0.96).
• BP6: Variant 14-23396676-G-A is Benign according to our data. Variant chr14-23396676-G-A is described in ClinVar as Benign. ClinVar VariationId is 258709.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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 rank	MANE	Protein	UniProt
MYH6	NM_002471.4	c.2292+18C>T		intron_variant	Intron 19 of 38	ENST00000405093.9	NP_002462.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MYH6	ENST00000405093.9	c.2292+18C>T		intron_variant	Intron 19 of 38	5	NM_002471.4	ENSP00000386041.3

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

GnomAD2 exomes AF: 0.328 AC: 82470 AN: 251054 AF XY: 0.328

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 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

African (AFR) AF: 0.634 AC: 21205 AN: 33472

American (AMR) AF: 0.237 AC: 10582 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.455 AC: 11880 AN: 26132

East Asian (EAS) AF: 0.147 AC: 5830 AN: 39700

South Asian (SAS) AF: 0.300 AC: 25889 AN: 86248

European-Finnish (FIN) AF: 0.270 AC: 14431 AN: 53406

Middle Eastern (MID) AF: 0.401 AC: 2310 AN: 5762

European-Non Finnish (NFE) AF: 0.357 AC: 397362 AN: 1111784

Other (OTH) AF: 0.365 AC: 22061 AN: 60378

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

African (AFR) AF: 0.624 AC: 25906 AN: 41510

American (AMR) AF: 0.316 AC: 4824 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.454 AC: 1575 AN: 3468

East Asian (EAS) AF: 0.162 AC: 837 AN: 5172

South Asian (SAS) AF: 0.295 AC: 1423 AN: 4830

European-Finnish (FIN) AF: 0.268 AC: 2838 AN: 10594

Middle Eastern (MID) AF: 0.391 AC: 115 AN: 294

European-Non Finnish (NFE) AF: 0.360 AC: 24499 AN: 67978

Other (OTH) AF: 0.425 AC: 899 AN: 2116

Alfa AF: 0.368 Hom.: 34193

Bravo AF: 0.425

Asia WGS AF: 0.283 AC: 985 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:5

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Clinical Genetics, Academic Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hypertrophic cardiomyopathy 14 Benign:1

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.96
CADD	Benign	0.0020
DANN	Benign	0.15
PhyloP100		-1.6
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: rs452036; hg19: chr14-23865885; COSMIC: COSV62449823; COSMIC: COSV62449823;