chr14-23386640-C-T

Variant names:

• chr14-23386640-C-T
• rs2071634
• NM_002471.4:c.4651-17G>A

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.4651-17G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.275 in 1,461,826 control chromosomes in the GnomAD database, including 53,508 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.24 (4408 hom., cov: 30)
  • Exomes 𝑓: 0.28 (49100 hom.)
• Consequence: MYH6 NM_002471.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -3.10
• 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=-0.85).
• BP6: Variant 14-23386640-C-T is Benign according to our data. Variant chr14-23386640-C-T is described in ClinVar as Benign. ClinVar VariationId is 258711.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.349 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002471.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MYH6	NM_002471.4	MANE Select	c.4651-17G>A		intron	N/A	NP_002462.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MYH6	ENST00000405093.9	TSL:5 MANE Select	c.4651-17G>A		intron	N/A	ENSP00000386041.3
	MYH6	ENST00000968262.1		c.4684-17G>A		intron	N/A	ENSP00000638321.1
	MYH6	ENST00000968257.1		c.4651-17G>A		intron	N/A	ENSP00000638316.1

Frequencies

GnomAD3 genomes AF: 0.239 AC: 35818 AN: 150064 Hom.: 4403 Cov.: 30

Gnomad AFR AF: 0.190

Gnomad AMI AF: 0.363

Gnomad AMR AF: 0.243

Gnomad ASJ AF: 0.342

Gnomad EAS AF: 0.187

Gnomad SAS AF: 0.363

Gnomad FIN AF: 0.222

Gnomad MID AF: 0.348

Gnomad NFE AF: 0.256

Gnomad OTH AF: 0.280

GnomAD2 exomes AF: 0.249 AC: 59829 AN: 240322 AF XY: 0.260

Gnomad AFR exome AF: 0.187

Gnomad AMR exome AF: 0.173

Gnomad ASJ exome AF: 0.328

Gnomad EAS exome AF: 0.178

Gnomad FIN exome AF: 0.216

Gnomad NFE exome AF: 0.264

Gnomad OTH exome AF: 0.268

GnomAD4 exome AF: 0.279 AC: 366391 AN: 1311638 Hom.: 49100 Cov.: 34 AF XY: 0.282 AC XY: 184800 AN XY: 654186

African (AFR) AF: 0.203 AC: 6097 AN: 30038

American (AMR) AF: 0.187 AC: 7956 AN: 42556

Ashkenazi Jewish (ASJ) AF: 0.349 AC: 8137 AN: 23336

East Asian (EAS) AF: 0.201 AC: 6949 AN: 34650

South Asian (SAS) AF: 0.360 AC: 29508 AN: 81986

European-Finnish (FIN) AF: 0.242 AC: 11319 AN: 46856

Middle Eastern (MID) AF: 0.350 AC: 1866 AN: 5332

European-Non Finnish (NFE) AF: 0.282 AC: 279717 AN: 993224

Other (OTH) AF: 0.277 AC: 14842 AN: 53660

GnomAD4 genome AF: 0.239 AC: 35850 AN: 150188 Hom.: 4408 Cov.: 30 AF XY: 0.238 AC XY: 17506 AN XY: 73406

African (AFR) AF: 0.190 AC: 7789 AN: 41014

American (AMR) AF: 0.243 AC: 3677 AN: 15138

Ashkenazi Jewish (ASJ) AF: 0.342 AC: 1183 AN: 3456

East Asian (EAS) AF: 0.188 AC: 937 AN: 4996

South Asian (SAS) AF: 0.363 AC: 1686 AN: 4642

European-Finnish (FIN) AF: 0.222 AC: 2241 AN: 10086

Middle Eastern (MID) AF: 0.337 AC: 99 AN: 294

European-Non Finnish (NFE) AF: 0.256 AC: 17320 AN: 67582

Other (OTH) AF: 0.284 AC: 592 AN: 2082

Alfa AF: 0.247 Hom.: 918

Bravo AF: 0.234

Asia WGS AF: 0.261 AC: 908 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (4)
-	-	2	not provided (2)
-	-	1	Hypertrophic cardiomyopathy 14 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	0.054
DANN	Benign	0.76
PhyloP100		-3.1
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: rs2071634; hg19: chr14-23855849; COSMIC: COSV62449567; COSMIC: COSV62449567;