17-10535374-C-T

Variant names:

• chr17-10535374-C-T
• rs3744566
• NM_017534.6:c.1975-9G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_017534.6(MYH2):​c.1975-9G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0599 in 1,611,432 control chromosomes in the GnomAD database, including 3,300 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.065 (356 hom., cov: 32)
  • Exomes 𝑓: 0.059 (2944 hom.)
• Consequence: MYH2 NM_017534.6 intron
• Scores: Splicing: ADA: 0.00002611
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -2.93
• Publications: 6 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 (BayesDel_noAF=-0.67).
• BP6: Variant 17-10535374-C-T is Benign according to our data. Variant chr17-10535374-C-T is described in ClinVar as Benign. ClinVar VariationId is 260816.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.116 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYH2	NM_017534.6	c.1975-9G>A		intron_variant	Intron 17 of 39	ENST00000245503.10	NP_060004.3
MYH2	NM_001100112.2	c.1975-9G>A		intron_variant	Intron 17 of 39		NP_001093582.1
MYHAS	NR_125367.1	n.168-32163C>T		intron_variant	Intron 2 of 10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MYH2	ENST00000245503.10	c.1975-9G>A		intron_variant	Intron 17 of 39	1	NM_017534.6	ENSP00000245503.5

Frequencies

GnomAD3 genomes AF: 0.0645 AC: 9803 AN: 152018 Hom.: 348 Cov.: 32

Gnomad AFR AF: 0.0800

Gnomad AMI AF: 0.0581

Gnomad AMR AF: 0.0488

Gnomad ASJ AF: 0.0804

Gnomad EAS AF: 0.0458

Gnomad SAS AF: 0.124

Gnomad FIN AF: 0.0525

Gnomad MID AF: 0.0728

Gnomad NFE AF: 0.0566

Gnomad OTH AF: 0.0761

GnomAD2 exomes AF: 0.0625 AC: 15663 AN: 250592 AF XY: 0.0652

Gnomad AFR exome AF: 0.0819

Gnomad AMR exome AF: 0.0448

Gnomad ASJ exome AF: 0.0828

Gnomad EAS exome AF: 0.0404

Gnomad FIN exome AF: 0.0544

Gnomad NFE exome AF: 0.0549

Gnomad OTH exome AF: 0.0602

GnomAD4 exome AF: 0.0594 AC: 86662 AN: 1459296 Hom.: 2944 Cov.: 31 AF XY: 0.0609 AC XY: 44219 AN XY: 726134

African (AFR) AF: 0.0824 AC: 2753 AN: 33428

American (AMR) AF: 0.0453 AC: 2024 AN: 44706

Ashkenazi Jewish (ASJ) AF: 0.0830 AC: 2168 AN: 26120

East Asian (EAS) AF: 0.0377 AC: 1496 AN: 39678

South Asian (SAS) AF: 0.112 AC: 9630 AN: 86188

European-Finnish (FIN) AF: 0.0537 AC: 2866 AN: 53386

Middle Eastern (MID) AF: 0.0586 AC: 338 AN: 5768

European-Non Finnish (NFE) AF: 0.0554 AC: 61532 AN: 1109714

Other (OTH) AF: 0.0639 AC: 3855 AN: 60308

GnomAD4 genome AF: 0.0647 AC: 9846 AN: 152136 Hom.: 356 Cov.: 32 AF XY: 0.0657 AC XY: 4888 AN XY: 74360

African (AFR) AF: 0.0808 AC: 3352 AN: 41500

American (AMR) AF: 0.0487 AC: 744 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.0804 AC: 279 AN: 3472

East Asian (EAS) AF: 0.0455 AC: 235 AN: 5164

South Asian (SAS) AF: 0.124 AC: 598 AN: 4814

European-Finnish (FIN) AF: 0.0525 AC: 556 AN: 10586

Middle Eastern (MID) AF: 0.0748 AC: 22 AN: 294

European-Non Finnish (NFE) AF: 0.0566 AC: 3846 AN: 68002

Other (OTH) AF: 0.0762 AC: 161 AN: 2112

Alfa AF: 0.0578 Hom.: 498

Bravo AF: 0.0635

Asia WGS AF: 0.0920 AC: 321 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

-

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Clinical Genetics, Academic Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Myopathy, proximal, and ophthalmoplegia Benign:2

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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. -

not provided Benign:2

Jul 15, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.67
CADD	Benign	1.3
DANN	Benign	0.74
PhyloP100		-2.9
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000026
dbscSNV1_RF	Benign	0.036
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: rs3744566; hg19: chr17-10438691; COSMIC: COSV55439443; COSMIC: COSV55439443;