17-10521326-C-T

Variant names:

• chr17-10521326-C-T
• rs34161789
• NM_017534.6:c.5780G>A

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 1P and 20B. PP3 BP4_Strong BP6_Very_Strong BS1 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1927W) has been classified as Uncertain significance.

• 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
• Publications: 15 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 -19 ACMG points.

• 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 Benign/Likely_benign. ClinVar VariationId is 197420.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 = 0.00446 (679/152282) while in subpopulation NFE AF = 0.00651 (443/68022). AF 95% confidence interval is 0.00601. There are 6 homozygotes in GnomAd4. There are 300 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 6 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.5780G>A	p.Arg1927Gln	missense	Exon 40 of 40	NP_060004.3
	MYH2	NM_001100112.2		c.5780G>A	p.Arg1927Gln	missense	Exon 40 of 40	NP_001093582.1	Q9UKX2-1
	MYHAS	NR_125367.1		n.168-46211C>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.5780G>A	p.Arg1927Gln	missense	Exon 40 of 40	ENSP00000245503.5	Q9UKX2-1
	MYH2	ENST00000532183.6	TSL:1	c.2081G>A	p.Arg694Gln	missense	Exon 17 of 17	ENSP00000433944.1	Q9UKX2-2
	MYH2	ENST00000622564.4	TSL:1	c.2081G>A	p.Arg694Gln	missense	Exon 18 of 18	ENSP00000482463.1	Q9UKX2-2

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

GnomAD2 exomes AF: 0.00410 AC: 1031 AN: 251444 AF XY: 0.00445

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 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

African (AFR) AF: 0.000956 AC: 32 AN: 33480

American (AMR) AF: 0.00293 AC: 131 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.000880 AC: 23 AN: 26136

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39696

South Asian (SAS) AF: 0.00333 AC: 287 AN: 86258

European-Finnish (FIN) AF: 0.00303 AC: 162 AN: 53416

Middle Eastern (MID) AF: 0.000348 AC: 2 AN: 5748

European-Non Finnish (NFE) AF: 0.00757 AC: 8422 AN: 1111992

Other (OTH) AF: 0.00596 AC: 360 AN: 60392

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

African (AFR) AF: 0.00120 AC: 50 AN: 41562

American (AMR) AF: 0.00530 AC: 81 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.000864 AC: 3 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5172

South Asian (SAS) AF: 0.00269 AC: 13 AN: 4826

European-Finnish (FIN) AF: 0.00330 AC: 35 AN: 10612

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

European-Non Finnish (NFE) AF: 0.00651 AC: 443 AN: 68022

Other (OTH) AF: 0.00520 AC: 11 AN: 2116

Alfa AF: 0.00577 Hom.: 3

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

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

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
DEOGEN2	Uncertain	0.50	D
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	0.98
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.93	D
MetaRNN	Benign	0.011	T
MetaSVM	Uncertain	0.69	D
MutationAssessor	Pathogenic	4.3	H
PhyloP100		7.9
PrimateAI	Uncertain	0.69	T
PROVEAN	Benign	-0.50	N
REVEL	Uncertain	0.51
Sift	Pathogenic	0.0	D
Sift4G	Benign	1.0	T
Polyphen		1.0	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
Mutation Taster		=89/11	polymorphism

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