rs267606904

chr14-23392968-C-G

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 1P and 5B. PP2 BP6 BS2

The NM_002471.4(MYH6):c.3195G>C(p.Gln1065His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000124 in 1,614,216 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00015 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00012 (0 hom.)
• Consequence: MYH6 NM_002471.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:6 B:4
• Conservation: PhyloP100: 0.0440

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]

ACMG classification

Verdict is Likely_benign. Variant got -4 ACMG points.

• PP2: Missense variant where missense usually causes diseases, MYH6
• BP6: Variant 14-23392968-C-G is Benign according to our data. Variant chr14-23392968-C-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 14149.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=6, Likely_benign=2}. Variant chr14-23392968-C-G is described in Lovd as [Likely_benign].
• BS2: High AC in GnomAd at 23 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MYH6	NM_002471.4	c.3195G>C	p.Gln1065His	missense_variant	24/39	ENST00000405093.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYH6	ENST00000405093.9	c.3195G>C	p.Gln1065His	missense_variant	24/39	5	NM_002471.4	P1

Frequencies

GnomAD3 genomes AF: 0.000151 AC: 23 AN: 152206 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000577

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00104

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000118

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000302 AC: 76 AN: 251494 Hom.: 0 AF XY: 0.000280 AC XY: 38 AN XY: 135922

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00130

Gnomad SAS exome AF: 0.000261

Gnomad FIN exome AF: 0.00162

Gnomad NFE exome AF: 0.0000791

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000121 AC: 177 AN: 1461892 Hom.: 0 Cov.: 32 AF XY: 0.000135 AC XY: 98 AN XY: 727248

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.00101

Gnomad4 SAS exome AF: 0.000209

Gnomad4 FIN exome AF: 0.00133

Gnomad4 NFE exome AF: 0.0000369

Gnomad4 OTH exome AF: 0.0000662

GnomAD4 genome AF: 0.000151 AC: 23 AN: 152324 Hom.: 0 Cov.: 32 AF XY: 0.000148 AC XY: 11 AN XY: 74486

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000578

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00104

Gnomad4 NFE AF: 0.000118

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000108 Hom.: 0

Bravo AF: 0.0000793

ExAC AF: 0.000231 AC: 28

Asia WGS AF: 0.00202 AC: 7 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:6 Benign:4

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:2 Benign:2

Likely benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Jul 26, 2023	In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 23861362, 28518168, 15998695, 34426522, 34697898, 35621855, 34045587, 27788187) -
Uncertain significance, criteria provided, single submitter	clinical testing	Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute	-	- -

Hypertrophic cardiomyopathy 14 Pathogenic:1 Uncertain:1 Benign:1

Pathogenic, no assertion criteria provided	literature only	OMIM	Jul 05, 2005	- -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Dec 18, 2022	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Mar 18, 2015

The p.Gln1065His variant in MYH6 has been reported in 2 individuals with HCM (Ca rniel 2005, Ng 2013) and has been identified by our laboratory in 1 individual w ith HCM and 1 individual with LVNC. This variant has also been identified in 0.1 % (11/8654) of East Asian chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs267606904). Computational prediction to ols and conservation analysis do not provide strong support for or against an im pact to the protein although the variant amino acid is present in several specie s (birds), raising the possibility that the change may be tolerated. In summary, the clinical significance of the p.Gln1065His variant is uncertain. -

Primary dilated cardiomyopathy;C0018991:Hemiplegia;C0149931:Migraine Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Nov 24, 2014

- -

Hypertrophic cardiomyopathy Uncertain:1

Uncertain significance, criteria provided, single submitter

research

Biesecker Lab/Clinical Genomics Section, National Institutes of Health

Apr 05, 2018

- -

Cardiovascular phenotype Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 18, 2019

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.36
BayesDel_addAF	Benign	0.00046	T
BayesDel_noAF	Pathogenic	0.19
Cadd	Benign	22
Dann	Uncertain	1.0
DEOGEN2	Uncertain	0.73	D;D
Eigen	Uncertain	0.47
Eigen_PC	Uncertain	0.39
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Uncertain	0.91	D;.
M_CAP	Uncertain	0.13	D
MetaRNN	Uncertain	0.51	D;D
MetaSVM	Uncertain	0.78	D
MutationAssessor	Uncertain	2.2	M;M
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.74	T
PROVEAN	Uncertain	-3.8	D;D
REVEL	Pathogenic	0.81
Sift	Uncertain	0.018	D;D
Sift4G	Benign	0.087	T;T
Polyphen		1.0	D;D
Vest4		0.68
MutPred		0.72		Gain of catalytic residue at L1063 (P = 0.0393);Gain of catalytic residue at L1063 (P = 0.0393);
MVP		0.94
MPC		1.0
ClinPred		0.17	T
GERP RS		3.9
Varity_R		0.50
gMVP		0.53

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

Publications

LitVar

Other links and lift over

dbSNP: rs267606904; hg19: chr14-23862177;