chr17-10529864-C-T

Variant names:

• chr17-10529864-C-T
• rs143872329
• NM_017534.6:c.2908G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 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
• Publications: 4 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 -20 ACMG points.

• 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 Benign/Likely_benign. ClinVar VariationId is 195769.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00462 (703/152222) while in subpopulation NFE AF = 0.00744 (506/68018). AF 95% confidence interval is 0.0069. There are 3 homozygotes in GnomAd4. There are 340 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 3 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.2908G>A	p.Val970Ile	missense	Exon 23 of 40	NP_060004.3
	MYH2	NM_001100112.2		c.2908G>A	p.Val970Ile	missense	Exon 23 of 40	NP_001093582.1
	MYHAS	NR_125367.1		n.168-37673C>T		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MYH2	ENST00000245503.10	TSL:1 MANE Select	c.2908G>A	p.Val970Ile	missense	Exon 23 of 40	ENSP00000245503.5
	MYH2	ENST00000532183.6	TSL:1	c.1974+6666G>A		intron	N/A	ENSP00000433944.1
	MYH2	ENST00000622564.4	TSL:1	c.1974+6666G>A		intron	N/A	ENSP00000482463.1

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

GnomAD2 exomes AF: 0.00528 AC: 1326 AN: 251240 AF XY: 0.00544

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 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

African (AFR) AF: 0.00140 AC: 47 AN: 33478

American (AMR) AF: 0.00181 AC: 81 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00386 AC: 101 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.00584 AC: 504 AN: 86252

European-Finnish (FIN) AF: 0.00569 AC: 304 AN: 53418

Middle Eastern (MID) AF: 0.00106 AC: 6 AN: 5652

European-Non Finnish (NFE) AF: 0.00861 AC: 9572 AN: 1111842

Other (OTH) AF: 0.00734 AC: 443 AN: 60384

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

African (AFR) AF: 0.00123 AC: 51 AN: 41516

American (AMR) AF: 0.00307 AC: 47 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.00288 AC: 10 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.00623 AC: 30 AN: 4818

European-Finnish (FIN) AF: 0.00490 AC: 52 AN: 10614

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

European-Non Finnish (NFE) AF: 0.00744 AC: 506 AN: 68018

Other (OTH) AF: 0.00332 AC: 7 AN: 2110

Alfa AF: 0.00652 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

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

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
Eigen	Uncertain	0.66
Eigen_PC	Uncertain	0.64
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.90	D
MetaRNN	Benign	0.011	T
MetaSVM	Uncertain	0.56	D
MutationAssessor	Uncertain	2.8	M
PhyloP100		5.8
PrimateAI	Pathogenic	0.81	D
PROVEAN	Benign	-0.81	N
REVEL	Pathogenic	0.69
Sift	Uncertain	0.0020	D
Sift4G	Benign	0.21	T
Polyphen		0.95	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
Mutation Taster		=23/77	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: rs143872329; hg19: chr17-10433181;