14-23397504-A-G

Variant names:

• chr14-23397504-A-G
• rs412768
• NM_002471.4:c.1962+39T>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.1962+39T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.31 in 1,605,766 control chromosomes in the GnomAD database, including 80,271 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.35 (9778 hom., cov: 33)
  • Exomes 𝑓: 0.31 (70493 hom.)
• Consequence: MYH6 NM_002471.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -2.77
• 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: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant 14-23397504-A-G is Benign according to our data. Variant chr14-23397504-A-G is described in ClinVar as Benign. ClinVar VariationId is 258707.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.47 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYH6	NM_002471.4	c.1962+39T>C		intron_variant	Intron 16 of 38	ENST00000405093.9	NP_002462.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MYH6	ENST00000405093.9	c.1962+39T>C		intron_variant	Intron 16 of 38	5	NM_002471.4	ENSP00000386041.3

Frequencies

GnomAD3 genomes AF: 0.347 AC: 52791 AN: 152070 Hom.: 9742 Cov.: 33

Gnomad AFR AF: 0.475

Gnomad AMI AF: 0.283

Gnomad AMR AF: 0.265

Gnomad ASJ AF: 0.409

Gnomad EAS AF: 0.163

Gnomad SAS AF: 0.273

Gnomad FIN AF: 0.260

Gnomad MID AF: 0.351

Gnomad NFE AF: 0.318

Gnomad OTH AF: 0.350

GnomAD2 exomes AF: 0.289 AC: 72491 AN: 251200 AF XY: 0.289

Gnomad AFR exome AF: 0.474

Gnomad AMR exome AF: 0.191

Gnomad ASJ exome AF: 0.398

Gnomad EAS exome AF: 0.165

Gnomad FIN exome AF: 0.255

Gnomad NFE exome AF: 0.311

Gnomad OTH exome AF: 0.308

GnomAD4 exome AF: 0.306 AC: 445140 AN: 1453578 Hom.: 70493 Cov.: 30 AF XY: 0.305 AC XY: 220879 AN XY: 723650

African (AFR) AF: 0.489 AC: 16271 AN: 33288

American (AMR) AF: 0.199 AC: 8887 AN: 44710

Ashkenazi Jewish (ASJ) AF: 0.407 AC: 10621 AN: 26084

East Asian (EAS) AF: 0.148 AC: 5864 AN: 39652

South Asian (SAS) AF: 0.276 AC: 23783 AN: 86098

European-Finnish (FIN) AF: 0.261 AC: 13884 AN: 53282

Middle Eastern (MID) AF: 0.340 AC: 1910 AN: 5620

European-Non Finnish (NFE) AF: 0.312 AC: 344748 AN: 1104734

Other (OTH) AF: 0.319 AC: 19172 AN: 60110

GnomAD4 genome AF: 0.347 AC: 52866 AN: 152188 Hom.: 9778 Cov.: 33 AF XY: 0.343 AC XY: 25507 AN XY: 74396

African (AFR) AF: 0.475 AC: 19726 AN: 41508

American (AMR) AF: 0.265 AC: 4054 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.409 AC: 1417 AN: 3468

East Asian (EAS) AF: 0.163 AC: 844 AN: 5170

South Asian (SAS) AF: 0.272 AC: 1314 AN: 4830

European-Finnish (FIN) AF: 0.260 AC: 2753 AN: 10592

Middle Eastern (MID) AF: 0.340 AC: 100 AN: 294

European-Non Finnish (NFE) AF: 0.318 AC: 21650 AN: 68002

Other (OTH) AF: 0.355 AC: 750 AN: 2110

Alfa AF: 0.345 Hom.: 7510

Bravo AF: 0.352

Asia WGS AF: 0.247 AC: 861 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	-0.90
CADD	Benign	0.036
DANN	Benign	0.15
PhyloP100		-2.8
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs412768; hg19: chr14-23866713; COSMIC: COSV62448801; COSMIC: COSV62448801;