rs138393827

Variant names:

• chr17-10524954-G-T
• rs138393827
• NM_017534.6:c.4774C>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.4774C>A​(p.Leu1592Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00169 in 1,614,042 control chromosomes in the GnomAD database, including 35 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0011 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0018 (35 hom.)
• Consequence: MYH2 NM_017534.6 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts P:1 B:7
• Conservation: PhyloP100: -0.436
• 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=0.009239972).
• BP6: Variant 17-10524954-G-T is Benign according to our data. Variant chr17-10524954-G-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 260825.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.00107 (163/152192) while in subpopulation SAS AF = 0.012 (58/4814). AF 95% confidence interval is 0.00957. There are 0 homozygotes in GnomAd4. There are 86 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 35 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MYH2	NM_017534.6	MANE Select	c.4774C>A	p.Leu1592Met	missense	Exon 34 of 40	NP_060004.3
	MYH2	NM_001100112.2		c.4774C>A	p.Leu1592Met	missense	Exon 34 of 40	NP_001093582.1
	MYHAS	NR_125367.1		n.168-42583G>T		intron	N/A

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MYH2	ENST00000245503.10	TSL:1 MANE Select	c.4774C>A	p.Leu1592Met	missense	Exon 34 of 40	ENSP00000245503.5
	MYH2	ENST00000532183.6	TSL:1	c.1975-3522C>A		intron	N/A	ENSP00000433944.1
	MYH2	ENST00000622564.4	TSL:1	c.1975-3522C>A		intron	N/A	ENSP00000482463.1

Frequencies

GnomAD3 genomes AF: 0.00107 AC: 163 AN: 152074 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000362

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000917

Gnomad ASJ AF: 0.000576

Gnomad EAS AF: 0.000579

Gnomad SAS AF: 0.0120

Gnomad FIN AF: 0.000284

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000956

Gnomad OTH AF: 0.00143

GnomAD2 exomes AF: 0.00270 AC: 678 AN: 251450 AF XY: 0.00353

Gnomad AFR exome AF: 0.000431

Gnomad AMR exome AF: 0.000578

Gnomad ASJ exome AF: 0.000595

Gnomad EAS exome AF: 0.000272

Gnomad FIN exome AF: 0.000647

Gnomad NFE exome AF: 0.00101

Gnomad OTH exome AF: 0.00179

GnomAD4 exome AF: 0.00176 AC: 2571 AN: 1461850 Hom.: 35 Cov.: 33 AF XY: 0.00219 AC XY: 1595 AN XY: 727228

African (AFR) AF: 0.000358 AC: 12 AN: 33480

American (AMR) AF: 0.000738 AC: 33 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.000574 AC: 15 AN: 26136

East Asian (EAS) AF: 0.000605 AC: 24 AN: 39700

South Asian (SAS) AF: 0.0164 AC: 1414 AN: 86252

European-Finnish (FIN) AF: 0.000712 AC: 38 AN: 53394

Middle Eastern (MID) AF: 0.00451 AC: 26 AN: 5768

European-Non Finnish (NFE) AF: 0.000798 AC: 887 AN: 1112000

Other (OTH) AF: 0.00202 AC: 122 AN: 60396

GnomAD4 genome AF: 0.00107 AC: 163 AN: 152192 Hom.: 0 Cov.: 32 AF XY: 0.00116 AC XY: 86 AN XY: 74388

African (AFR) AF: 0.000361 AC: 15 AN: 41528

American (AMR) AF: 0.000916 AC: 14 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.000576 AC: 2 AN: 3470

East Asian (EAS) AF: 0.000580 AC: 3 AN: 5172

South Asian (SAS) AF: 0.0120 AC: 58 AN: 4814

European-Finnish (FIN) AF: 0.000284 AC: 3 AN: 10582

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

European-Non Finnish (NFE) AF: 0.000956 AC: 65 AN: 68016

Other (OTH) AF: 0.00142 AC: 3 AN: 2116

Alfa AF: 0.000825 Hom.: 0

Bravo AF: 0.000854

TwinsUK AF: 0.000809 AC: 3

ALSPAC AF: 0.00104 AC: 4

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.00140 AC: 12

ExAC AF: 0.00314 AC: 381

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.081
BayesDel_addAF	Benign	-0.42	T
BayesDel_noAF	Benign	-0.36
CADD	Benign	16
DANN	Benign	0.95
DEOGEN2	Benign	0.32	T
Eigen	Benign	-0.77
Eigen_PC	Benign	-0.70
FATHMM_MKL	Benign	0.61	D
LIST_S2	Benign	0.53	T
MetaRNN	Benign	0.0092	T
MetaSVM	Benign	-0.64	T
MutationAssessor	Benign	1.9	L
PhyloP100		-0.44
PrimateAI	Benign	0.38	T
PROVEAN	Benign	-0.73	N
REVEL	Benign	0.15
Sift	Benign	0.091	T
Sift4G	Benign	0.22	T
Polyphen		0.015	B
Vest4		0.22
MVP		0.52
MPC		0.35
ClinPred		0.0027	T
GERP RS		1.3
Varity_R		0.096
gMVP		0.13
Mutation Taster		=98/2	disease causing (ClinVar)

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: rs138393827; hg19: chr17-10428271; COSMIC: COSV106082549;