17-10521326-C-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 2P and 16B. PP2 PP3 BP4_Strong BP6_Very_Strong BS2

The NM_017534.6(MYH2):c.5780G>A(p.Arg1927Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00626 in 1,614,124 control chromosomes in the GnomAD database, including 52 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. R1927R) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0045 (6 hom., cov: 32)
  • Exomes 𝑓: 0.0064 (46 hom.)
• Consequence: MYH2 NM_017534.6 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 7.91

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 -14 ACMG points.

• PP2: Missense variant where missense usually causes diseases, MYH2
• PP3: Multiple lines of computational evidence support a deleterious effect 7: BayesDel_noAF, Cadd, Dann, Eigen, FATHMM_MKL, MutationAssessor, phyloP100way_vertebrate [when AlphaMissense, max_spliceai, MetaRNN, MutationTaster was below the threshold]
• BP4: Computational evidence support a benign effect (MetaRNN=0.011096537).
• BP6: Variant 17-10521326-C-T is Benign according to our data. Variant chr17-10521326-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 197420.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Homozygotes in GnomAd at 6 SD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MYH2	NM_017534.6	c.5780G>A	p.Arg1927Gln	missense_variant	40/40	ENST00000245503.10
MYHAS	NR_125367.1	n.168-46211C>T		intron_variant, non_coding_transcript_variant
MYH2	NM_001100112.2	c.5780G>A	p.Arg1927Gln	missense_variant	40/40

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYH2	ENST00000245503.10	c.5780G>A	p.Arg1927Gln	missense_variant	40/40	1	NM_017534.6	P1
	ENST00000399342.6	n.207-11998C>T		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes AF: 0.00446 AC: 679 AN: 152164 Hom.: 6 Cov.: 32

Gnomad AFR AF: 0.00121

Gnomad AMI AF: 0.0471

Gnomad AMR AF: 0.00530

Gnomad ASJ AF: 0.000864

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00269

Gnomad FIN AF: 0.00330

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00651

Gnomad OTH AF: 0.00525

GnomAD3 exomes AF: 0.00410 AC: 1031 AN: 251444 Hom.: 7 AF XY: 0.00445 AC XY: 605 AN XY: 135886

Gnomad AFR exome AF: 0.00117

Gnomad AMR exome AF: 0.00243

Gnomad ASJ exome AF: 0.000893

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.00307

Gnomad FIN exome AF: 0.00236

Gnomad NFE exome AF: 0.00653

Gnomad OTH exome AF: 0.00489

GnomAD4 exome AF: 0.00644 AC: 9421 AN: 1461842 Hom.: 46 Cov.: 31 AF XY: 0.00629 AC XY: 4574 AN XY: 727226

Gnomad4 AFR exome AF: 0.000956

Gnomad4 AMR exome AF: 0.00293

Gnomad4 ASJ exome AF: 0.000880

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.00333

Gnomad4 FIN exome AF: 0.00303

Gnomad4 NFE exome AF: 0.00757

Gnomad4 OTH exome AF: 0.00596

GnomAD4 genome AF: 0.00446 AC: 679 AN: 152282 Hom.: 6 Cov.: 32 AF XY: 0.00403 AC XY: 300 AN XY: 74464

Gnomad4 AFR AF: 0.00120

Gnomad4 AMR AF: 0.00530

Gnomad4 ASJ AF: 0.000864

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00269

Gnomad4 FIN AF: 0.00330

Gnomad4 NFE AF: 0.00651

Gnomad4 OTH AF: 0.00520

Alfa AF: 0.00600 Hom.: 1

Bravo AF: 0.00466

TwinsUK AF: 0.00863 AC: 32

ALSPAC AF: 0.00701 AC: 27

ESP6500AA AF: 0.00136 AC: 6

ESP6500EA AF: 0.00744 AC: 64

ExAC AF: 0.00415 AC: 504

Asia WGS AF: 0.00318 AC: 11 AN: 3478

EpiCase AF: 0.00687

EpiControl AF: 0.00735

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Nov 07, 2016	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Dec 01, 2023	MYH2: BS2 -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 23, 2020	This variant is associated with the following publications: (PMID: 15741996) -

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Nov 15, 2014	- -
Likely benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Aug 07, 2020	- -

MYH2-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Apr 09, 2019

This variant is classified as 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

Invitae

Jan 29, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.34
BayesDel_addAF	Uncertain	0.12	D
BayesDel_noAF	Pathogenic	0.40
Cadd	Pathogenic	32
Dann	Pathogenic	1.0
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	0.98
FATHMM_MKL	Pathogenic	0.99	D
MetaRNN	Benign	0.011	T;T;T;T
MetaSVM	Uncertain	0.69	D
MutationTaster	Benign	0.92	D;D;D
PrimateAI	Uncertain	0.69	T
PROVEAN	Benign	-0.50	N;D;D;.
REVEL	Uncertain	0.51
Sift	Pathogenic	0.0	D;D;D;.
Sift4G	Benign	1.0	T;D;D;T
Polyphen		1.0	.;D;D;.
Vest4		0.81
MVP		0.98
MPC		1.0
ClinPred		0.15	T
GERP RS		5.5
Varity_R		0.37
gMVP		0.23

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: rs34161789; hg19: chr17-10424643; COSMIC: COSV55450500; COSMIC: COSV55450500;