rs61739663

Positions:

• chr17-10525735-G-A

Variant summary

Our verdict is Benign. Variant got -17 ACMG points: 0P and 17B. BP4_Strong BP6_Very_Strong BP7 BS2

The NM_017534.6(MYH2):​c.4329C>T​(p.Ala1443=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00601 in 1,614,174 control chromosomes in the GnomAD database, including 39 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0045 (2 hom., cov: 33)
  • Exomes 𝑓: 0.0062 (37 hom.)
• Consequence: MYH2 NM_017534.6 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -1.18

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 -17 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BP6: Variant 17-10525735-G-A is Benign according to our data. Variant chr17-10525735-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 465941.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-10525735-G-A is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-1.18 with no splicing effect.
• BS2: High Homozygotes in GnomAd4 at 2 SD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MYH2	NM_017534.6	c.4329C>T	p.Ala1443=	synonymous_variant	31/40	ENST00000245503.10
MYHAS	NR_125367.1	n.168-41802G>A		intron_variant, non_coding_transcript_variant
MYH2	NM_001100112.2	c.4329C>T	p.Ala1443=	synonymous_variant	31/40

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYH2	ENST00000245503.10	c.4329C>T	p.Ala1443=	synonymous_variant	31/40	1	NM_017534.6	P1
	ENST00000399342.6	n.207-7589G>A		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes AF: 0.00453 AC: 690 AN: 152168 Hom.: 2 Cov.: 33

Gnomad AFR AF: 0.00386

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00524

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000377

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.00626

Gnomad OTH AF: 0.00813

GnomAD3 exomes AF: 0.00377 AC: 948 AN: 251408 Hom.: 3 AF XY: 0.00381 AC XY: 518 AN XY: 135874

Gnomad AFR exome AF: 0.00338

Gnomad AMR exome AF: 0.00257

Gnomad ASJ exome AF: 0.0000992

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.000970

Gnomad NFE exome AF: 0.00669

Gnomad OTH exome AF: 0.00343

GnomAD4 exome AF: 0.00616 AC: 9012 AN: 1461888 Hom.: 37 Cov.: 33 AF XY: 0.00582 AC XY: 4231 AN XY: 727242

Gnomad4 AFR exome AF: 0.00293

Gnomad4 AMR exome AF: 0.00259

Gnomad4 ASJ exome AF: 0.0000765

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00155

Gnomad4 NFE exome AF: 0.00751

Gnomad4 OTH exome AF: 0.00581

GnomAD4 genome AF: 0.00452 AC: 688 AN: 152286 Hom.: 2 Cov.: 33 AF XY: 0.00428 AC XY: 319 AN XY: 74464

Gnomad4 AFR AF: 0.00385

Gnomad4 AMR AF: 0.00523

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000377

Gnomad4 NFE AF: 0.00623

Gnomad4 OTH AF: 0.00804

Alfa AF: 0.00515 Hom.: 4

Bravo AF: 0.00495

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00545

EpiControl AF: 0.00528

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2024	MYH2: BP4, BP7, BS2 -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 14, 2020	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

Sep 30, 2016

- -

MYH2-related disorder Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 01, 2019

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Myopathy, proximal, and ophthalmoplegia Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 30, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	0.086
DANN	Benign	0.88

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: rs61739663; hg19: chr17-10429052;