chr17-10524607-G-A

Variant names:

• chr17-10524607-G-A
• rs1042236
• NM_017534.6:c.5034C>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_017534.6(MYH2):​c.5034C>T​(p.Ala1678Ala) 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:8
• Conservation: PhyloP100: 1.14
• Publications: 13 publications found

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]

MYHAS (HGNC:50609): (myosin heavy chain gene cluster antisense RNA) Predicted to enable primary miRNA binding activity. Predicted to be involved in response to muscle activity and skeletal muscle fiber development. Predicted to act upstream of or within with a positive effect on gene expression. Predicted to be located in cytoplasm and nucleus. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Benign. The variant received -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 VariationId is 260826.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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 rank	MANE	Protein	UniProt
MYH2	NM_017534.6	c.5034C>T	p.Ala1678Ala	synonymous_variant	Exon 35 of 40	ENST00000245503.10	NP_060004.3
MYH2	NM_001100112.2	c.5034C>T	p.Ala1678Ala	synonymous_variant	Exon 35 of 40		NP_001093582.1
MYHAS	NR_125367.1	n.168-42930G>A		intron_variant	Intron 2 of 10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MYH2	ENST00000245503.10	c.5034C>T	p.Ala1678Ala	synonymous_variant	Exon 35 of 40	1	NM_017534.6	ENSP00000245503.5

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

GnomAD2 exomes AF: 0.266 AC: 66885 AN: 251154 AF XY: 0.257

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 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

African (AFR) AF: 0.102 AC: 3431 AN: 33480

American (AMR) AF: 0.454 AC: 20308 AN: 44704

Ashkenazi Jewish (ASJ) AF: 0.204 AC: 5344 AN: 26136

East Asian (EAS) AF: 0.741 AC: 29400 AN: 39698

South Asian (SAS) AF: 0.316 AC: 27267 AN: 86250

European-Finnish (FIN) AF: 0.200 AC: 10672 AN: 53420

Middle Eastern (MID) AF: 0.191 AC: 1101 AN: 5768

European-Non Finnish (NFE) AF: 0.146 AC: 162597 AN: 1111818

Other (OTH) AF: 0.200 AC: 12101 AN: 60394

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

African (AFR) AF: 0.109 AC: 4548 AN: 41540

American (AMR) AF: 0.313 AC: 4786 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.215 AC: 745 AN: 3468

East Asian (EAS) AF: 0.731 AC: 3768 AN: 5152

South Asian (SAS) AF: 0.327 AC: 1575 AN: 4814

European-Finnish (FIN) AF: 0.208 AC: 2199 AN: 10576

Middle Eastern (MID) AF: 0.204 AC: 60 AN: 294

European-Non Finnish (NFE) AF: 0.151 AC: 10242 AN: 67992

Other (OTH) AF: 0.183 AC: 386 AN: 2110

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:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

-

Clinical Genetics, Academic Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Aug 25, 2015

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:2

Jul 15, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Myopathy, proximal, and ophthalmoplegia Benign:2

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.47
CADD	Benign	7.3
DANN	Benign	0.80
PhyloP100		1.1
Mutation Taster		=97/3	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: rs1042236; hg19: chr17-10427924; COSMIC: COSV55439398;