rs34935550

Variant names:

• chr14-23389488-C-G
• rs34935550
• NM_002471.4:c.3883G>C

Your query was ambiguous. Multiple possible variants found:

• chr14-23389488-C-G
• chr14-23389488-C-T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_002471.4(MYH6):​c.3883G>C​(p.Glu1295Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0031 in 1,614,204 control chromosomes in the GnomAD database, including 21 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0027 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0031 (20 hom.)
• Consequence: MYH6 NM_002471.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:16
• Conservation: PhyloP100: 7.76
• Publications: 17 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):

• MYH-6 related congenital heart defects

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• hypertrophic cardiomyopathy 14

  Inheritance: AD Classification: STRONG, LIMITED Submitted by: Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae)
• 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: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.010231346).
• BP6: Variant 14-23389488-C-G is Benign according to our data. Variant chr14-23389488-C-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 44492.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.00272 (415/152310) while in subpopulation EAS AF = 0.0166 (86/5184). AF 95% confidence interval is 0.0138. There are 1 homozygotes in GnomAd4. There are 199 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 415 AD gene.

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.3883G>C	p.Glu1295Gln	missense	Exon 28 of 39	NP_002462.2	P13533

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MYH6	ENST00000405093.9	TSL:5 MANE Select	c.3883G>C	p.Glu1295Gln	missense	Exon 28 of 39	ENSP00000386041.3	P13533
	MYH6	ENST00000968262.1		c.3916G>C	p.Glu1306Gln	missense	Exon 28 of 39	ENSP00000638321.1
	MYH6	ENST00000968257.1		c.3883G>C	p.Glu1295Gln	missense	Exon 28 of 39	ENSP00000638316.1

Frequencies

GnomAD3 genomes AF: 0.00273 AC: 415 AN: 152192 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000603

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00308

Gnomad ASJ AF: 0.00173

Gnomad EAS AF: 0.0166

Gnomad SAS AF: 0.00269

Gnomad FIN AF: 0.000283

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.00331

Gnomad OTH AF: 0.00335

GnomAD2 exomes AF: 0.00329 AC: 828 AN: 251476 AF XY: 0.00316

Gnomad AFR exome AF: 0.000246

Gnomad AMR exome AF: 0.00234

Gnomad ASJ exome AF: 0.00188

Gnomad EAS exome AF: 0.0165

Gnomad FIN exome AF: 0.000139

Gnomad NFE exome AF: 0.00291

Gnomad OTH exome AF: 0.00309

GnomAD4 exome AF: 0.00314 AC: 4590 AN: 1461894 Hom.: 20 Cov.: 33 AF XY: 0.00306 AC XY: 2226 AN XY: 727248

African (AFR) AF: 0.000717 AC: 24 AN: 33480

American (AMR) AF: 0.00250 AC: 112 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00149 AC: 39 AN: 26136

East Asian (EAS) AF: 0.0125 AC: 496 AN: 39700

South Asian (SAS) AF: 0.00220 AC: 190 AN: 86258

European-Finnish (FIN) AF: 0.000225 AC: 12 AN: 53420

Middle Eastern (MID) AF: 0.00277 AC: 16 AN: 5768

European-Non Finnish (NFE) AF: 0.00313 AC: 3486 AN: 1112012

Other (OTH) AF: 0.00356 AC: 215 AN: 60396

GnomAD4 genome AF: 0.00272 AC: 415 AN: 152310 Hom.: 1 Cov.: 32 AF XY: 0.00267 AC XY: 199 AN XY: 74468

African (AFR) AF: 0.000601 AC: 25 AN: 41572

American (AMR) AF: 0.00307 AC: 47 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.00173 AC: 6 AN: 3470

East Asian (EAS) AF: 0.0166 AC: 86 AN: 5184

South Asian (SAS) AF: 0.00269 AC: 13 AN: 4828

European-Finnish (FIN) AF: 0.000283 AC: 3 AN: 10614

Middle Eastern (MID) AF: 0.0102 AC: 3 AN: 294

European-Non Finnish (NFE) AF: 0.00331 AC: 225 AN: 68020

Other (OTH) AF: 0.00331 AC: 7 AN: 2114

Alfa AF: 0.00183 Hom.: 0

Bravo AF: 0.00308

TwinsUK AF: 0.00405 AC: 15

ALSPAC AF: 0.00285 AC: 11

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00442 AC: 38

ExAC AF: 0.00325 AC: 394

Asia WGS AF: 0.00577 AC: 20 AN: 3478

EpiCase AF: 0.00349

EpiControl AF: 0.00284

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	7	not specified (7)
-	-	5	not provided (5)
-	-	1	Cardiomyopathy (1)
-	-	1	Cardiovascular phenotype (1)
-	-	1	Hypertrophic cardiomyopathy 14 (1)
-	-	1	Hypertrophic cardiomyopathy;C0007196:Restrictive cardiomyopathy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.36
BayesDel_addAF	Benign	-0.23	T
BayesDel_noAF	Benign	-0.10
CADD	Uncertain	26
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.66	D
Eigen	Pathogenic	0.86
Eigen_PC	Pathogenic	0.78
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.96	D
MetaRNN	Benign	0.010	T
MetaSVM	Uncertain	0.50	D
MutationAssessor	Pathogenic	3.0	M
PhyloP100		7.8
PrimateAI	Uncertain	0.57	T
PROVEAN	Benign	-2.1	N
REVEL	Pathogenic	0.77
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.031	D
Polyphen		0.99	D
Vest4		0.42
MVP		0.93
MPC		0.79
ClinPred		0.017	T
GERP RS		4.6
Varity_R		0.28
gMVP		0.44
Mutation Taster		=76/24	polymorphism

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: rs34935550; hg19: chr14-23858697; COSMIC: COSV62451268; COSMIC: COSV62451268;