rs138393827

Positions:

• chr17-10524954-G-T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2 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. 15/20 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

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]

(HGNC:):

ACMG classification

Verdict is Benign. Variant got -19 ACMG points.

• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), MYH2. . Gene score misZ 1.9724 (greater than the threshold 3.09). Trascript score misZ 4.733 (greater than threshold 3.09). GenCC has associacion of gene with childhood-onset autosomal recessive myopathy with external ophthalmoplegia, hereditary inclusion body myopathy-joint contractures-ophthalmoplegia syndrome, myopathy, proximal, and ophthalmoplegia.
• 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 [Likely_benign]. Clinvar id 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_exome allele frequency = 0.00176 (2571/1461850) while in subpopulation SAS AF= 0.0164 (1414/86252). AF 95% confidence interval is 0.0157. There are 35 homozygotes in gnomad4_exome. There are 1595 alleles in male gnomad4_exome subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome4 at 35 SD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MYH2	NM_017534.6	c.4774C>A	p.Leu1592Met	missense_variant	34/40	ENST00000245503.10	NP_060004.3
MYHAS	NR_125367.1	n.168-42583G>T		intron_variant, non_coding_transcript_variant
MYH2	NM_001100112.2	c.4774C>A	p.Leu1592Met	missense_variant	34/40		NP_001093582.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MYH2	ENST00000245503.10	c.4774C>A	p.Leu1592Met	missense_variant	34/40	1	NM_017534.6	ENSP00000245503	P1
	ENST00000399342.6	n.207-8370G>T		intron_variant, non_coding_transcript_variant		3

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

GnomAD3 exomes AF: 0.00270 AC: 678 AN: 251450 Hom.: 11 AF XY: 0.00353 AC XY: 480 AN XY: 135896

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 SAS exome AF: 0.0163

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

Gnomad4 AFR exome AF: 0.000358

Gnomad4 AMR exome AF: 0.000738

Gnomad4 ASJ exome AF: 0.000574

Gnomad4 EAS exome AF: 0.000605

Gnomad4 SAS exome AF: 0.0164

Gnomad4 FIN exome AF: 0.000712

Gnomad4 NFE exome AF: 0.000798

Gnomad4 OTH exome AF: 0.00202

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

Gnomad4 AFR AF: 0.000361

Gnomad4 AMR AF: 0.000916

Gnomad4 ASJ AF: 0.000576

Gnomad4 EAS AF: 0.000580

Gnomad4 SAS AF: 0.0120

Gnomad4 FIN AF: 0.000284

Gnomad4 NFE AF: 0.000956

Gnomad4 OTH AF: 0.00142

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

Significance: Benign/Likely benign

Submissions summary: Pathogenic:1 Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Myopathy, proximal, and ophthalmoplegia Pathogenic:1 Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 15, 2024	- -
Likely pathogenic, flagged submission	clinical testing	NeuroMeGen, Hospital Clinico Santiago de Compostela	Oct 08, 2018	- -

not specified Benign:3

Likely benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Aug 16, 2018	- -

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 21, 2023	See Variant Classification Assertion Criteria. -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -

Computational scores

Source: dbNSFP v4.3

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;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;T
MetaSVM	Benign	-0.64	T
MutationAssessor	Benign	1.9	L;L
MutationTaster	Benign	1.0	D;N;N
PrimateAI	Benign	0.38	T
PROVEAN	Benign	-0.73	N;N
REVEL	Benign	0.15
Sift	Benign	0.091	T;T
Sift4G	Benign	0.22	T;T
Polyphen		0.015	B;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

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

Publications

LitVar

Other links and lift over

dbSNP: rs138393827; hg19: chr17-10428271;