rs142586585

Positions:

• chr17-10529418-G-C

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 1P and 9B. PP2 BP4_Strong BP6 BS2

The ENST00000245503.10(MYH2):​c.3181C>G​(p.Leu1061Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00339 in 1,614,156 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0022 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0035 (7 hom.)
• Consequence: MYH2 ENST00000245503.10 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:7
• Conservation: PhyloP100: 7.70

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 -8 ACMG points.

• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), MYH2. . Gene score misZ 1.9724 (greater than the threshold 3.09). Trascript score misZ 4.733 (greater than threshold 3.09). GenCC has associacion of gene with childhood-onset autosomal recessive myopathy with external ophthalmoplegia, hereditary inclusion body myopathy-joint contractures-ophthalmoplegia syndrome, myopathy, proximal, and ophthalmoplegia.
• BP4: Computational evidence support a benign effect (MetaRNN=0.055102527).
• BP6: Variant 17-10529418-G-C is Benign according to our data. Variant chr17-10529418-G-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 195897.We mark this variant Likely_benign, oryginal submissions are: {Benign=2, Likely_benign=4, Uncertain_significance=1}. Variant chr17-10529418-G-C is described in Lovd as [Likely_benign].
• BS2: High Homozygotes in GnomAdExome4 at 7 SD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MYH2	NM_017534.6	c.3181C>G	p.Leu1061Val	missense_variant	25/40	ENST00000245503.10	NP_060004.3
MYHAS	NR_125367.1	n.168-38119G>C		intron_variant, non_coding_transcript_variant
MYH2	NM_001100112.2	c.3181C>G	p.Leu1061Val	missense_variant	25/40		NP_001093582.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MYH2	ENST00000245503.10	c.3181C>G	p.Leu1061Val	missense_variant	25/40	1	NM_017534.6	ENSP00000245503	P1
	ENST00000399342.6	n.207-3906G>C		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes AF: 0.00218 AC: 331 AN: 152160 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000627

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00190

Gnomad ASJ AF: 0.00576

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000622

Gnomad FIN AF: 0.000189

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00368

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.00198 AC: 498 AN: 251268 Hom.: 1 AF XY: 0.00207 AC XY: 281 AN XY: 135788

Gnomad AFR exome AF: 0.000738

Gnomad AMR exome AF: 0.000723

Gnomad ASJ exome AF: 0.00576

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000686

Gnomad FIN exome AF: 0.0000924

Gnomad NFE exome AF: 0.00326

Gnomad OTH exome AF: 0.00163

GnomAD4 exome AF: 0.00352 AC: 5147 AN: 1461878 Hom.: 7 Cov.: 34 AF XY: 0.00338 AC XY: 2461 AN XY: 727236

Gnomad4 AFR exome AF: 0.000448

Gnomad4 AMR exome AF: 0.000827

Gnomad4 ASJ exome AF: 0.00501

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000684

Gnomad4 FIN exome AF: 0.000131

Gnomad4 NFE exome AF: 0.00422

Gnomad4 OTH exome AF: 0.00343

GnomAD4 genome AF: 0.00217 AC: 331 AN: 152278 Hom.: 0 Cov.: 32 AF XY: 0.00193 AC XY: 144 AN XY: 74454

Gnomad4 AFR AF: 0.000626

Gnomad4 AMR AF: 0.00190

Gnomad4 ASJ AF: 0.00576

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000622

Gnomad4 FIN AF: 0.000189

Gnomad4 NFE AF: 0.00368

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.00349 Hom.: 3

Bravo AF: 0.00215

TwinsUK AF: 0.00270 AC: 10

ALSPAC AF: 0.00363 AC: 14

ESP6500AA AF: 0.000908 AC: 4

ESP6500EA AF: 0.00419 AC: 36

ExAC AF: 0.00195 AC: 237

EpiCase AF: 0.00420

EpiControl AF: 0.00320

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:7

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Myopathy, proximal, and ophthalmoplegia Uncertain:1 Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 29, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Feb 16, 2018	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. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -
Benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2024	MYH2: BS1, BS2 -
Likely benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	May 07, 2019	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 08, 2021	This variant is associated with the following publications: (PMID: 15741996, 22349865) -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

Apr 15, 2015

- -

MYH2-related disorder Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

May 17, 2024

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). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Uncertain	0.11	D
BayesDel_noAF	Pathogenic	0.38
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.51	D;D
Eigen	Uncertain	0.54
Eigen_PC	Uncertain	0.54
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.87	.;D
M_CAP	Benign	0.081	D
MetaRNN	Benign	0.055	T;T
MetaSVM	Uncertain	0.72	D
MutationAssessor	Uncertain	2.3	M;M
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.70	T
PROVEAN	Uncertain	-2.4	N;N
REVEL	Pathogenic	0.71
Sift	Uncertain	0.0010	D;D
Sift4G	Benign	0.27	T;T
Polyphen		0.96	P;P
Vest4		0.85
MVP		0.95
MPC		0.61
ClinPred		0.074	T
GERP RS		5.2
Varity_R		0.45
gMVP		0.17

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: rs142586585; hg19: chr17-10432735;