rs142586585

Variant names:

• chr17-10529418-G-C
• rs142586585
• NM_017534.6:c.3181C>G

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_017534.6(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 NM_017534.6 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:7
• Conservation: PhyloP100: 7.70
• Publications: 6 publications found

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:50609): (myosin heavy chain gene cluster antisense RNA) Predicted to enable primary miRNA binding activity. Predicted to be involved in response to muscle activity and skeletal muscle fiber development. Predicted to act upstream of or within with a positive effect on gene expression. Predicted to be located in cytoplasm and nucleus. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Benign. The variant received -13 ACMG points.

• 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 VariationId is 195897.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00217 (331/152278) while in subpopulation NFE AF = 0.00368 (250/68014). AF 95% confidence interval is 0.0033. There are 0 homozygotes in GnomAd4. There are 144 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 7 SD,AR,AD gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_017534.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MYH2	NM_017534.6	MANE Select	c.3181C>G	p.Leu1061Val	missense	Exon 25 of 40	NP_060004.3
	MYH2	NM_001100112.2		c.3181C>G	p.Leu1061Val	missense	Exon 25 of 40	NP_001093582.1	Q9UKX2-1
	MYHAS	NR_125367.1		n.168-38119G>C		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MYH2	ENST00000245503.10	TSL:1 MANE Select	c.3181C>G	p.Leu1061Val	missense	Exon 25 of 40	ENSP00000245503.5	Q9UKX2-1
	MYH2	ENST00000532183.6	TSL:1	c.1974+7112C>G		intron	N/A	ENSP00000433944.1	Q9UKX2-2
	MYH2	ENST00000622564.4	TSL:1	c.1974+7112C>G		intron	N/A	ENSP00000482463.1	Q9UKX2-2

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

GnomAD2 exomes AF: 0.00198 AC: 498 AN: 251268 AF XY: 0.00207

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 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

African (AFR) AF: 0.000448 AC: 15 AN: 33480

American (AMR) AF: 0.000827 AC: 37 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00501 AC: 131 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39696

South Asian (SAS) AF: 0.000684 AC: 59 AN: 86256

European-Finnish (FIN) AF: 0.000131 AC: 7 AN: 53414

Middle Eastern (MID) AF: 0.000173 AC: 1 AN: 5768

European-Non Finnish (NFE) AF: 0.00422 AC: 4690 AN: 1112010

Other (OTH) AF: 0.00343 AC: 207 AN: 60396

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

African (AFR) AF: 0.000626 AC: 26 AN: 41566

American (AMR) AF: 0.00190 AC: 29 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.00576 AC: 20 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.000622 AC: 3 AN: 4822

European-Finnish (FIN) AF: 0.000189 AC: 2 AN: 10604

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00368 AC: 250 AN: 68014

Other (OTH) AF: 0.000473 AC: 1 AN: 2112

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

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	2	Myopathy, proximal, and ophthalmoplegia (3)
-	-	3	not provided (3)
-	-	1	MYH2-related disorder (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

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
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
MetaSVM	Uncertain	0.72	D
MutationAssessor	Uncertain	2.3	M
PhyloP100		7.7
PrimateAI	Uncertain	0.70	T
PROVEAN	Uncertain	-2.4	N
REVEL	Pathogenic	0.71
Sift	Uncertain	0.0010	D
Sift4G	Benign	0.27	T
Polyphen		0.96	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
Mutation Taster		=17/83	disease causing

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

Other links and lift over

dbSNP: rs142586585; hg19: chr17-10432735;