rs1042236

chr17-10524607-G-A

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_017534.6(MYH2):c.5034C>T(p.Ala1678=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.186 in 1,613,808 control chromosomes in the GnomAD database, including 39,588 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.19 (3900 hom., cov: 33)
  • Exomes 𝑓: 0.19 (35688 hom.)
• Consequence: MYH2 NM_017534.6 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 1.14

Genes affected

MYH2 (HGNC:7572): (myosin heavy chain 2) Myosins are actin-based motor proteins that function in the generation of mechanical force in eukaryotic cells. Muscle myosins are heterohexamers composed of 2 myosin heavy chains and 2 pairs of nonidentical myosin light chains. This gene encodes a member of the class II or conventional myosin heavy chains, and functions in skeletal muscle contraction. This gene is found in a cluster of myosin heavy chain genes on chromosome 17. A mutation in this gene results in inclusion body myopathy-3. Multiple alternatively spliced variants, encoding the same protein, have been identified. [provided by RefSeq, Sep 2009]

(HGNC:):

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.47).
• BP6: Variant 17-10524607-G-A is Benign according to our data. Variant chr17-10524607-G-A is described in ClinVar as [Benign]. Clinvar id is 260826.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-10524607-G-A is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=1.14 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.712 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MYH2	NM_017534.6	c.5034C>T	p.Ala1678=	synonymous_variant	35/40	ENST00000245503.10
MYHAS	NR_125367.1	n.168-42930G>A		intron_variant, non_coding_transcript_variant
MYH2	NM_001100112.2	c.5034C>T	p.Ala1678=	synonymous_variant	35/40

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYH2	ENST00000245503.10	c.5034C>T	p.Ala1678=	synonymous_variant	35/40	1	NM_017534.6	P1
	ENST00000399342.6	n.207-8717G>A		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes AF: 0.187 AC: 28453 AN: 152020 Hom.: 3897 Cov.: 33

Gnomad AFR AF: 0.110

Gnomad AMI AF: 0.178

Gnomad AMR AF: 0.313

Gnomad ASJ AF: 0.215

Gnomad EAS AF: 0.732

Gnomad SAS AF: 0.328

Gnomad FIN AF: 0.208

Gnomad MID AF: 0.197

Gnomad NFE AF: 0.151

Gnomad OTH AF: 0.181

GnomAD3 exomes AF: 0.266 AC: 66885 AN: 251154 Hom.: 13128 AF XY: 0.257 AC XY: 34862 AN XY: 135758

Gnomad AFR exome AF: 0.109

Gnomad AMR exome AF: 0.475

Gnomad ASJ exome AF: 0.204

Gnomad EAS exome AF: 0.751

Gnomad SAS exome AF: 0.315

Gnomad FIN exome AF: 0.202

Gnomad NFE exome AF: 0.154

Gnomad OTH exome AF: 0.219

GnomAD4 exome AF: 0.186 AC: 272221 AN: 1461668 Hom.: 35688 Cov.: 35 AF XY: 0.189 AC XY: 137073 AN XY: 727166

Gnomad4 AFR exome AF: 0.102

Gnomad4 AMR exome AF: 0.454

Gnomad4 ASJ exome AF: 0.204

Gnomad4 EAS exome AF: 0.741

Gnomad4 SAS exome AF: 0.316

Gnomad4 FIN exome AF: 0.200

Gnomad4 NFE exome AF: 0.146

Gnomad4 OTH exome AF: 0.200

GnomAD4 genome AF: 0.187 AC: 28471 AN: 152140 Hom.: 3900 Cov.: 33 AF XY: 0.198 AC XY: 14710 AN XY: 74354

Gnomad4 AFR AF: 0.109

Gnomad4 AMR AF: 0.313

Gnomad4 ASJ AF: 0.215

Gnomad4 EAS AF: 0.731

Gnomad4 SAS AF: 0.327

Gnomad4 FIN AF: 0.208

Gnomad4 NFE AF: 0.151

Gnomad4 OTH AF: 0.183

Alfa AF: 0.158 Hom.: 909

Bravo AF: 0.195

Asia WGS AF: 0.471 AC: 1635 AN: 3476

EpiCase AF: 0.152

EpiControl AF: 0.148

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Aug 25, 2015	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -

Myopathy, proximal, and ophthalmoplegia Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jul 15, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.47
Cadd	Benign	7.3
Dann	Benign	0.80

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: rs1042236; hg19: chr17-10427924; COSMIC: COSV55439398;