rs11658164

Variant names:

• chr17-10529472-A-C
• rs11658164
• NM_017534.6:c.3127T>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.3127T>G​(p.Ser1043Ala) variant causes a missense change. The variant allele was found at a frequency of 0.00192 in 1,614,128 control chromosomes in the GnomAD database, including 8 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S1043F) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0013 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0020 (7 hom.)
• Consequence: MYH2 NM_017534.6 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:5
• Conservation: PhyloP100: 7.11
• Publications: 5 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=0.023307532).
• BP6: Variant 17-10529472-A-C is Benign according to our data. Variant chr17-10529472-A-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 195898.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00126 (192/152238) while in subpopulation NFE AF = 0.00213 (145/68002). AF 95% confidence interval is 0.00185. There are 1 homozygotes in GnomAd4. There are 87 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.3127T>G	p.Ser1043Ala	missense	Exon 25 of 40	NP_060004.3
	MYH2	NM_001100112.2		c.3127T>G	p.Ser1043Ala	missense	Exon 25 of 40	NP_001093582.1
	MYHAS	NR_125367.1		n.168-38065A>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.3127T>G	p.Ser1043Ala	missense	Exon 25 of 40	ENSP00000245503.5
	MYH2	ENST00000532183.6	TSL:1	c.1974+7058T>G		intron	N/A	ENSP00000433944.1
	MYH2	ENST00000622564.4	TSL:1	c.1974+7058T>G		intron	N/A	ENSP00000482463.1

Frequencies

GnomAD3 genomes AF: 0.00126 AC: 192 AN: 152120 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000410

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000524

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00207

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00213

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00118 AC: 296 AN: 251352 AF XY: 0.00117

Gnomad AFR exome AF: 0.000800

Gnomad AMR exome AF: 0.000347

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00212

Gnomad NFE exome AF: 0.00187

Gnomad OTH exome AF: 0.00179

GnomAD4 exome AF: 0.00199 AC: 2910 AN: 1461890 Hom.: 7 Cov.: 34 AF XY: 0.00192 AC XY: 1395 AN XY: 727246

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

American (AMR) AF: 0.000470 AC: 21 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0000383 AC: 1 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.0000812 AC: 7 AN: 86258

European-Finnish (FIN) AF: 0.00288 AC: 154 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00235 AC: 2615 AN: 1112008

Other (OTH) AF: 0.00161 AC: 97 AN: 60396

GnomAD4 genome AF: 0.00126 AC: 192 AN: 152238 Hom.: 1 Cov.: 32 AF XY: 0.00117 AC XY: 87 AN XY: 74438

African (AFR) AF: 0.000409 AC: 17 AN: 41540

American (AMR) AF: 0.000523 AC: 8 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00207 AC: 22 AN: 10608

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.00213 AC: 145 AN: 68002

Other (OTH) AF: 0.00 AC: 0 AN: 2112

Alfa AF: 0.00166 Hom.: 1

Bravo AF: 0.00114

TwinsUK AF: 0.00189 AC: 7

ALSPAC AF: 0.00259 AC: 10

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00186 AC: 16

ExAC AF: 0.00135 AC: 164

EpiCase AF: 0.00191

EpiControl AF: 0.00178

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	2	2	not provided (4)
-	-	1	MYH2-related disorder (1)
-	-	1	Myopathy, proximal, and ophthalmoplegia (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Uncertain	-0.050
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Benign	0.34	T
Eigen	Uncertain	0.34
Eigen_PC	Uncertain	0.42
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.69	T
M_CAP	Benign	0.065	D
MetaRNN	Benign	0.023	T
MetaSVM	Uncertain	0.35	D
MutationAssessor	Uncertain	2.2	M
PhyloP100		7.1
PrimateAI	Uncertain	0.79	T
PROVEAN	Benign	-2.1	N
REVEL	Uncertain	0.47
Sift	Benign	0.10	T
Sift4G	Benign	0.24	T
Polyphen		0.38	B
Vest4		0.47
MVP		0.93
MPC		0.80
ClinPred		0.014	T
GERP RS		5.2
Varity_R		0.18
gMVP		0.24
Mutation Taster		=39/61	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: rs11658164; hg19: chr17-10432789;