rs113190032

Positions:

• chr17-10529714-T-C

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_017534.6(MYH2):​c.2967A>G​(p.Ala989=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00197 in 1,610,484 control chromosomes in the GnomAD database, including 88 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.010 (40 hom., cov: 32)
  • Exomes 𝑓: 0.0011 (48 hom.)
• Consequence: MYH2 NM_017534.6 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -0.748

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.54).
• BP6: Variant 17-10529714-T-C is Benign according to our data. Variant chr17-10529714-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 285372.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.748 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0103 (1553/150984) while in subpopulation AFR AF= 0.0343 (1387/40402). AF 95% confidence interval is 0.0328. There are 40 homozygotes in gnomad4. There are 753 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 40 SD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MYH2	NM_017534.6	c.2967A>G	p.Ala989=	synonymous_variant	24/40	ENST00000245503.10	NP_060004.3
MYHAS	NR_125367.1	n.168-37823T>C		intron_variant, non_coding_transcript_variant
MYH2	NM_001100112.2	c.2967A>G	p.Ala989=	synonymous_variant	24/40		NP_001093582.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MYH2	ENST00000245503.10	c.2967A>G	p.Ala989=	synonymous_variant	24/40	1	NM_017534.6	ENSP00000245503	P1
	ENST00000399342.6	n.207-3610T>C		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes AF: 0.0102 AC: 1539 AN: 150878 Hom.: 39 Cov.: 32

Gnomad AFR AF: 0.0341

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00532

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00798

Gnomad SAS AF: 0.00104

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000412

Gnomad OTH AF: 0.00482

GnomAD3 exomes AF: 0.00181 AC: 454 AN: 250272 Hom.: 18 AF XY: 0.00135 AC XY: 183 AN XY: 135352

Gnomad AFR exome AF: 0.0225

Gnomad AMR exome AF: 0.00128

Gnomad ASJ exome AF: 0.0000992

Gnomad EAS exome AF: 0.000554

Gnomad SAS exome AF: 0.000458

Gnomad FIN exome AF: 0.0000462

Gnomad NFE exome AF: 0.000264

Gnomad OTH exome AF: 0.000491

GnomAD4 exome AF: 0.00111 AC: 1613 AN: 1459500 Hom.: 48 Cov.: 34 AF XY: 0.000994 AC XY: 722 AN XY: 726136

Gnomad4 AFR exome AF: 0.0275

Gnomad4 AMR exome AF: 0.00186

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.00339

Gnomad4 SAS exome AF: 0.000696

Gnomad4 FIN exome AF: 0.000112

Gnomad4 NFE exome AF: 0.000280

Gnomad4 OTH exome AF: 0.00188

GnomAD4 genome AF: 0.0103 AC: 1553 AN: 150984 Hom.: 40 Cov.: 32 AF XY: 0.0102 AC XY: 753 AN XY: 73846

Gnomad4 AFR AF: 0.0343

Gnomad4 AMR AF: 0.00531

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00800

Gnomad4 SAS AF: 0.00104

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000412

Gnomad4 OTH AF: 0.00477

Alfa AF: 0.00440 Hom.: 6

Bravo AF: 0.0164

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 16, 2019	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	May 01, 2024	MYH2: BP4, BP7, BS1, BS2 -

Myopathy, proximal, and ophthalmoplegia Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Jan 13, 2022	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 19, 2024	- -
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. -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

Dec 22, 2015

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.54
CADD	Benign	3.3
DANN	Benign	0.81

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: rs113190032; hg19: chr17-10433031; COSMIC: COSV55433879;