rs719277

Positions:

• chr17-10542865-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_017534.6(MYH2):​c.904+10G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.428 in 1,539,660 control chromosomes in the GnomAD database, including 148,706 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.41 (13798 hom., cov: 33)
  • Exomes 𝑓: 0.43 (134908 hom.)
• Consequence: MYH2 NM_017534.6 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -0.929

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:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BP6: Variant 17-10542865-C-T is Benign according to our data. Variant chr17-10542865-C-T is described in ClinVar as [Benign]. Clinvar id is 260829.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-10542865-C-T is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.813 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MYH2	NM_017534.6	c.904+10G>A		intron_variant		ENST00000245503.10
MYHAS	NR_125367.1	n.168-24672C>T		intron_variant, non_coding_transcript_variant
MYH2	NM_001100112.2	c.904+10G>A		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYH2	ENST00000245503.10	c.904+10G>A		intron_variant		1	NM_017534.6	P1
MYH2	ENST00000532183.6	c.904+10G>A		intron_variant		1
MYH2	ENST00000622564.4	c.904+10G>A		intron_variant		1
MYH2	ENST00000397183.6	c.904+10G>A		intron_variant		5		P1

Frequencies

GnomAD3 genomes AF: 0.412 AC: 62530 AN: 151876 Hom.: 13786 Cov.: 33

Gnomad AFR AF: 0.306

Gnomad AMI AF: 0.455

Gnomad AMR AF: 0.488

Gnomad ASJ AF: 0.448

Gnomad EAS AF: 0.834

Gnomad SAS AF: 0.616

Gnomad FIN AF: 0.452

Gnomad MID AF: 0.442

Gnomad NFE AF: 0.403

Gnomad OTH AF: 0.410

GnomAD3 exomes AF: 0.486 AC: 119756 AN: 246534 Hom.: 31373 AF XY: 0.485 AC XY: 64730 AN XY: 133338

Gnomad AFR exome AF: 0.301

Gnomad AMR exome AF: 0.598

Gnomad ASJ exome AF: 0.452

Gnomad EAS exome AF: 0.848

Gnomad SAS exome AF: 0.595

Gnomad FIN exome AF: 0.447

Gnomad NFE exome AF: 0.402

Gnomad OTH exome AF: 0.442

GnomAD4 exome AF: 0.429 AC: 595951 AN: 1387666 Hom.: 134908 Cov.: 24 AF XY: 0.434 AC XY: 301360 AN XY: 694496

Gnomad4 AFR exome AF: 0.298

Gnomad4 AMR exome AF: 0.583

Gnomad4 ASJ exome AF: 0.452

Gnomad4 EAS exome AF: 0.830

Gnomad4 SAS exome AF: 0.593

Gnomad4 FIN exome AF: 0.438

Gnomad4 NFE exome AF: 0.397

Gnomad4 OTH exome AF: 0.436

GnomAD4 genome AF: 0.412 AC: 62583 AN: 151994 Hom.: 13798 Cov.: 33 AF XY: 0.424 AC XY: 31486 AN XY: 74284

Gnomad4 AFR AF: 0.307

Gnomad4 AMR AF: 0.488

Gnomad4 ASJ AF: 0.448

Gnomad4 EAS AF: 0.834

Gnomad4 SAS AF: 0.616

Gnomad4 FIN AF: 0.452

Gnomad4 NFE AF: 0.403

Gnomad4 OTH AF: 0.408

Alfa AF: 0.407 Hom.: 14524

Bravo AF: 0.407

Asia WGS AF: 0.652 AC: 2259 AN: 3470

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Myopathy, proximal, and ophthalmoplegia Benign:4

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Sep 05, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
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. -

not specified Benign:3

Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

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	-0.85
CADD	Benign	0.90
DANN	Benign	0.54

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: rs719277; hg19: chr17-10446182; COSMIC: COSV55450958; COSMIC: COSV55450958;