rs146615128

chr17-10525822-G-Achr17-10525822-G-T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BS1 BS2

The NM_017534.6(MYH2):c.4242C>T(p.Asn1414=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000929 in 1,614,108 control chromosomes in the GnomAD database, including 18 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0051 (9 hom., cov: 33)
  • Exomes 𝑓: 0.00050 (9 hom.)
• Consequence: MYH2 NM_017534.6 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.589

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.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.43).
• BP6: Variant 17-10525822-G-A is Benign according to our data. Variant chr17-10525822-G-A is described in ClinVar as [Benign]. Clinvar id is 465939.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.589 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0051 (776/152240) while in subpopulation AFR AF= 0.0179 (742/41536). AF 95% confidence interval is 0.0168. There are 9 homozygotes in gnomad4. There are 362 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 9 SD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MYH2	NM_017534.6	c.4242C>T	p.Asn1414=	synonymous_variant	31/40	ENST00000245503.10
MYHAS	NR_125367.1	n.168-41715G>A		intron_variant, non_coding_transcript_variant
MYH2	NM_001100112.2	c.4242C>T	p.Asn1414=	synonymous_variant	31/40

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYH2	ENST00000245503.10	c.4242C>T	p.Asn1414=	synonymous_variant	31/40	1	NM_017534.6	P1
	ENST00000399342.6	n.207-7502G>A		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes AF: 0.00505 AC: 768 AN: 152122 Hom.: 9 Cov.: 33

Gnomad AFR AF: 0.0177

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00124

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00124

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.00287

GnomAD3 exomes AF: 0.00138 AC: 346 AN: 251288 Hom.: 2 AF XY: 0.000994 AC XY: 135 AN XY: 135800

Gnomad AFR exome AF: 0.0187

Gnomad AMR exome AF: 0.000665

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000425

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000176

Gnomad OTH exome AF: 0.000653

GnomAD4 exome AF: 0.000495 AC: 724 AN: 1461868 Hom.: 9 Cov.: 33 AF XY: 0.000455 AC XY: 331 AN XY: 727236

Gnomad4 AFR exome AF: 0.0175

Gnomad4 AMR exome AF: 0.000805

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000278

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000899

Gnomad4 OTH exome AF: 0.000993

GnomAD4 genome AF: 0.00510 AC: 776 AN: 152240 Hom.: 9 Cov.: 33 AF XY: 0.00486 AC XY: 362 AN XY: 74430

Gnomad4 AFR AF: 0.0179

Gnomad4 AMR AF: 0.00124

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00104

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000588

Gnomad4 OTH AF: 0.00284

Alfa AF: 0.00205 Hom.: 2

Bravo AF: 0.00587

Asia WGS AF: 0.00202 AC: 7 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Myopathy, proximal, and ophthalmoplegia 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	Invitae	Jan 28, 2024	- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Oct 18, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.43
Cadd	Benign	0.85
Dann	Benign	0.89

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs146615128; hg19: chr17-10429139; COSMIC: COSV99819286;