14-23386269-C-G

Variant names:

• chr14-23386269-C-G
• rs396024
• NM_002471.4:c.4959+46G>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.4959+46G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0998 in 1,613,660 control chromosomes in the GnomAD database, including 9,196 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.076 (540 hom., cov: 31)
  • Exomes 𝑓: 0.10 (8656 hom.)
• Consequence: MYH6 NM_002471.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.401
• Publications: 7 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=-0.84).
• BP6: Variant 14-23386269-C-G is Benign according to our data. Variant chr14-23386269-C-G is described in ClinVar as Benign. ClinVar VariationId is 258712.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.11 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYH6	NM_002471.4	c.4959+46G>C		intron_variant	Intron 33 of 38	ENST00000405093.9	NP_002462.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MYH6	ENST00000405093.9	c.4959+46G>C		intron_variant	Intron 33 of 38	5	NM_002471.4	ENSP00000386041.3

Frequencies

GnomAD3 genomes AF: 0.0760 AC: 11566 AN: 152116 Hom.: 539 Cov.: 31

Gnomad AFR AF: 0.0309

Gnomad AMI AF: 0.0899

Gnomad AMR AF: 0.0547

Gnomad ASJ AF: 0.124

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.0317

Gnomad FIN AF: 0.0904

Gnomad MID AF: 0.0701

Gnomad NFE AF: 0.113

Gnomad OTH AF: 0.0718

GnomAD2 exomes AF: 0.0749 AC: 18709 AN: 249782 AF XY: 0.0755

Gnomad AFR exome AF: 0.0300

Gnomad AMR exome AF: 0.0356

Gnomad ASJ exome AF: 0.130

Gnomad EAS exome AF: 0.000272

Gnomad FIN exome AF: 0.0854

Gnomad NFE exome AF: 0.108

Gnomad OTH exome AF: 0.0900

GnomAD4 exome AF: 0.102 AC: 149548 AN: 1461424 Hom.: 8656 Cov.: 35 AF XY: 0.101 AC XY: 73126 AN XY: 726998

African (AFR) AF: 0.0272 AC: 909 AN: 33474

American (AMR) AF: 0.0373 AC: 1668 AN: 44708

Ashkenazi Jewish (ASJ) AF: 0.130 AC: 3392 AN: 26132

East Asian (EAS) AF: 0.000176 AC: 7 AN: 39700

South Asian (SAS) AF: 0.0395 AC: 3403 AN: 86238

European-Finnish (FIN) AF: 0.0840 AC: 4479 AN: 53326

Middle Eastern (MID) AF: 0.0731 AC: 420 AN: 5744

European-Non Finnish (NFE) AF: 0.116 AC: 129418 AN: 1111728

Other (OTH) AF: 0.0969 AC: 5852 AN: 60374

GnomAD4 genome AF: 0.0760 AC: 11569 AN: 152236 Hom.: 540 Cov.: 31 AF XY: 0.0746 AC XY: 5554 AN XY: 74424

African (AFR) AF: 0.0309 AC: 1286 AN: 41564

American (AMR) AF: 0.0547 AC: 837 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.124 AC: 430 AN: 3472

East Asian (EAS) AF: 0.000194 AC: 1 AN: 5164

South Asian (SAS) AF: 0.0317 AC: 153 AN: 4822

European-Finnish (FIN) AF: 0.0904 AC: 959 AN: 10608

Middle Eastern (MID) AF: 0.0714 AC: 21 AN: 294

European-Non Finnish (NFE) AF: 0.113 AC: 7650 AN: 67990

Other (OTH) AF: 0.0711 AC: 150 AN: 2110

Alfa AF: 0.0664 Hom.: 72

Bravo AF: 0.0726

Asia WGS AF: 0.0180 AC: 63 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	-0.84
CADD	Benign	1.2
DANN	Benign	0.67
PhyloP100		-0.40
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: rs396024; hg19: chr14-23855478;