rs16943488

Variant names:

• chr17-10521442-A-G
• rs16943488
• NM_017534.6:c.5674-10T>C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_017534.6(MYH2):​c.5674-10T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00217 in 1,613,816 control chromosomes in the GnomAD database, including 69 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.012 (41 hom., cov: 32)
  • Exomes 𝑓: 0.0012 (28 hom.)
• Consequence: MYH2 NM_017534.6 intron
• Scores: Splicing: ADA: 0.006412
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.770

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]

ENSG00000272736 (HGNC:):

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

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.47).
• BP6: Variant 17-10521442-A-G is Benign according to our data. Variant chr17-10521442-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 465949.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-10521442-A-G is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0118 (1796/152310) while in subpopulation AFR AF= 0.0416 (1728/41556). AF 95% confidence interval is 0.04. There are 41 homozygotes in gnomad4. There are 830 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 41 SD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYH2	NM_017534.6	c.5674-10T>C		intron_variant	Intron 39 of 39	ENST00000245503.10	NP_060004.3
MYH2	NM_001100112.2	c.5674-10T>C		intron_variant	Intron 39 of 39		NP_001093582.1
MYHAS	NR_125367.1	n.168-46095A>G		intron_variant	Intron 2 of 10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MYH2	ENST00000245503.10	c.5674-10T>C		intron_variant	Intron 39 of 39	1	NM_017534.6	ENSP00000245503.5

Frequencies

GnomAD3 genomes AF: 0.0118 AC: 1795 AN: 152192 Hom.: 41 Cov.: 32

Gnomad AFR AF: 0.0417

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00262

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0000882

Gnomad OTH AF: 0.00955

GnomAD3 exomes AF: 0.00314 AC: 788 AN: 251312 Hom.: 17 AF XY: 0.00225 AC XY: 305 AN XY: 135816

Gnomad AFR exome AF: 0.0436

Gnomad AMR exome AF: 0.00171

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000980

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000440

Gnomad OTH exome AF: 0.00196

GnomAD4 exome AF: 0.00116 AC: 1702 AN: 1461506 Hom.: 28 Cov.: 30 AF XY: 0.000989 AC XY: 719 AN XY: 727110

Gnomad4 AFR exome AF: 0.0423

Gnomad4 AMR exome AF: 0.00172

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000696

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000432

Gnomad4 OTH exome AF: 0.00235

GnomAD4 genome AF: 0.0118 AC: 1796 AN: 152310 Hom.: 41 Cov.: 32 AF XY: 0.0111 AC XY: 830 AN XY: 74488

Gnomad4 AFR AF: 0.0416

Gnomad4 AMR AF: 0.00261

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000882

Gnomad4 OTH AF: 0.00945

Alfa AF: 0.00827 Hom.: 9

Bravo AF: 0.0131

Asia WGS AF: 0.00231 AC: 8 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Myopathy, proximal, and ophthalmoplegia Benign:2

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:1

Dec 14, 2020

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.47
CADD	Benign	17
DANN	Benign	0.82

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0064
dbscSNV1_RF	Benign	0.086
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: rs16943488; hg19: chr17-10424759;