rs143872329

chr17-10529864-C-T

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 1P and 16B. PP2 BP4_Strong BP6_Very_Strong BS2

The NM_017534.6(MYH2):c.2908G>A(p.Val970Ile) variant causes a missense change. The variant allele was found at a frequency of 0.00729 in 1,613,804 control chromosomes in the GnomAD database, including 60 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V970A) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0046 (3 hom., cov: 32)
  • Exomes 𝑓: 0.0076 (57 hom.)
• Consequence: MYH2 NM_017534.6 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 5.85

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 -15 ACMG points.

• PP2: Missense variant where missense usually causes diseases, MYH2
• BP4: Computational evidence support a benign effect (MetaRNN=0.011111289).
• BP6: Variant 17-10529864-C-T is Benign according to our data. Variant chr17-10529864-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 195769.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Homozygotes in GnomAd at 3 SD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MYH2	NM_017534.6	c.2908G>A	p.Val970Ile	missense_variant	23/40	ENST00000245503.10
MYHAS	NR_125367.1	n.168-37673C>T		intron_variant, non_coding_transcript_variant
MYH2	NM_001100112.2	c.2908G>A	p.Val970Ile	missense_variant	23/40

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYH2	ENST00000245503.10	c.2908G>A	p.Val970Ile	missense_variant	23/40	1	NM_017534.6	P1
	ENST00000399342.6	n.207-3460C>T		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes AF: 0.00463 AC: 705 AN: 152104 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.00123

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00308

Gnomad ASJ AF: 0.00288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00664

Gnomad FIN AF: 0.00490

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00744

Gnomad OTH AF: 0.00335

GnomAD3 exomes AF: 0.00528 AC: 1326 AN: 251240 Hom.: 8 AF XY: 0.00544 AC XY: 739 AN XY: 135822

Gnomad AFR exome AF: 0.00117

Gnomad AMR exome AF: 0.00197

Gnomad ASJ exome AF: 0.00417

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00572

Gnomad FIN exome AF: 0.00513

Gnomad NFE exome AF: 0.00763

Gnomad OTH exome AF: 0.00718

GnomAD4 exome AF: 0.00757 AC: 11058 AN: 1461582 Hom.: 57 Cov.: 34 AF XY: 0.00740 AC XY: 5378 AN XY: 727046

Gnomad4 AFR exome AF: 0.00140

Gnomad4 AMR exome AF: 0.00181

Gnomad4 ASJ exome AF: 0.00386

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00584

Gnomad4 FIN exome AF: 0.00569

Gnomad4 NFE exome AF: 0.00861

Gnomad4 OTH exome AF: 0.00734

GnomAD4 genome AF: 0.00462 AC: 703 AN: 152222 Hom.: 3 Cov.: 32 AF XY: 0.00457 AC XY: 340 AN XY: 74426

Gnomad4 AFR AF: 0.00123

Gnomad4 AMR AF: 0.00307

Gnomad4 ASJ AF: 0.00288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00623

Gnomad4 FIN AF: 0.00490

Gnomad4 NFE AF: 0.00744

Gnomad4 OTH AF: 0.00332

Alfa AF: 0.00484 Hom.: 0

Bravo AF: 0.00410

ESP6500AA AF: 0.00159 AC: 7

ESP6500EA AF: 0.00561 AC: 48

ExAC AF: 0.00601 AC: 729

EpiCase AF: 0.00692

EpiControl AF: 0.00616

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Myopathy, proximal, and ophthalmoplegia Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 25, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2024	MYH2: PP3, BS1, BS2 -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 06, 2018	This variant is associated with the following publications: (PMID: 24082139, 15741996, 32140910) -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

Nov 21, 2014

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.39
BayesDel_addAF	Benign	-0.062	T
BayesDel_noAF	Pathogenic	0.14
Cadd	Uncertain	25
Dann	Uncertain	1.0
DEOGEN2	Benign	0.16	T;T
Eigen	Uncertain	0.66
Eigen_PC	Uncertain	0.64
FATHMM_MKL	Uncertain	0.94	D
MetaRNN	Benign	0.011	T;T
MetaSVM	Uncertain	0.56	D
MutationAssessor	Uncertain	2.8	M;M
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Pathogenic	0.81	D
PROVEAN	Benign	-0.81	N;N
REVEL	Pathogenic	0.69
Sift	Uncertain	0.0020	D;D
Sift4G	Benign	0.21	T;T
Polyphen		0.95	P;P
Vest4		0.76
MVP		0.90
MPC		1.2
ClinPred		0.056	T
GERP RS		5.2
Varity_R		0.37
gMVP		0.19

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: rs143872329; hg19: chr17-10433181;