rs76202964

Variant names:

• chr14-23396980-G-A
• rs76202964
• NM_002471.4:c.2151C>T

Your query was ambiguous. Multiple possible variants found:

• chr14-23396980-G-A
• chr14-23396980-G-T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_002471.4(MYH6):​c.2151C>T​(p.Tyr717Tyr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0153 in 1,613,146 control chromosomes in the GnomAD database, including 491 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.016 (53 hom., cov: 33)
  • Exomes 𝑓: 0.015 (438 hom.)
• Consequence: MYH6 NM_002471.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 0.0480
• Publications: 6 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.54).
• BP6: Variant 14-23396980-G-A is Benign according to our data. Variant chr14-23396980-G-A is described in ClinVar as Benign. ClinVar VariationId is 44461.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.048 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0752 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.2151C>T	p.Tyr717Tyr	synonymous	Exon 18 of 39	NP_002462.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MYH6	ENST00000405093.9	TSL:5 MANE Select	c.2151C>T	p.Tyr717Tyr	synonymous	Exon 18 of 39	ENSP00000386041.3
	MYH6	ENST00000968262.1		c.2184C>T	p.Tyr728Tyr	synonymous	Exon 18 of 39	ENSP00000638321.1
	MYH6	ENST00000968257.1		c.2151C>T	p.Tyr717Tyr	synonymous	Exon 18 of 39	ENSP00000638316.1

Frequencies

GnomAD3 genomes AF: 0.0161 AC: 2450 AN: 152198 Hom.: 44 Cov.: 33

Gnomad AFR AF: 0.00808

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0262

Gnomad ASJ AF: 0.0495

Gnomad EAS AF: 0.0816

Gnomad SAS AF: 0.0366

Gnomad FIN AF: 0.00612

Gnomad MID AF: 0.0791

Gnomad NFE AF: 0.0116

Gnomad OTH AF: 0.0301

GnomAD2 exomes AF: 0.0242 AC: 6093 AN: 251410 AF XY: 0.0243

Gnomad AFR exome AF: 0.00886

Gnomad AMR exome AF: 0.0363

Gnomad ASJ exome AF: 0.0397

Gnomad EAS exome AF: 0.0841

Gnomad FIN exome AF: 0.00651

Gnomad NFE exome AF: 0.0125

Gnomad OTH exome AF: 0.0280

GnomAD4 exome AF: 0.0152 AC: 22166 AN: 1460830 Hom.: 438 Cov.: 35 AF XY: 0.0159 AC XY: 11553 AN XY: 726738

African (AFR) AF: 0.00921 AC: 308 AN: 33438

American (AMR) AF: 0.0352 AC: 1576 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0420 AC: 1097 AN: 26136

East Asian (EAS) AF: 0.0859 AC: 3411 AN: 39700

South Asian (SAS) AF: 0.0320 AC: 2759 AN: 86202

European-Finnish (FIN) AF: 0.00567 AC: 303 AN: 53418

Middle Eastern (MID) AF: 0.0615 AC: 302 AN: 4910

European-Non Finnish (NFE) AF: 0.0100 AC: 11138 AN: 1111998

Other (OTH) AF: 0.0211 AC: 1272 AN: 60304

GnomAD4 genome AF: 0.0163 AC: 2478 AN: 152316 Hom.: 53 Cov.: 33 AF XY: 0.0172 AC XY: 1281 AN XY: 74472

African (AFR) AF: 0.00839 AC: 349 AN: 41576

American (AMR) AF: 0.0263 AC: 402 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.0495 AC: 172 AN: 3472

East Asian (EAS) AF: 0.0816 AC: 423 AN: 5182

South Asian (SAS) AF: 0.0369 AC: 178 AN: 4828

European-Finnish (FIN) AF: 0.00612 AC: 65 AN: 10624

Middle Eastern (MID) AF: 0.0680 AC: 20 AN: 294

European-Non Finnish (NFE) AF: 0.0116 AC: 788 AN: 68018

Other (OTH) AF: 0.0384 AC: 81 AN: 2112

Alfa AF: 0.0161 Hom.: 17

Bravo AF: 0.0187

Asia WGS AF: 0.0710 AC: 246 AN: 3478

EpiCase AF: 0.0172

EpiControl AF: 0.0168

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	6	not specified (6)
-	-	1	Cardiovascular phenotype (1)
-	-	1	Hypertrophic cardiomyopathy 14 (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.54
CADD	Benign	0.087
DANN	Benign	0.45
PhyloP100		0.048
Mutation Taster		=99/1	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: rs76202964; hg19: chr14-23866189; COSMIC: COSV62448797; COSMIC: COSV62448797;