17-10535412-T-C

Variant names:

• chr17-10535412-T-C
• rs3744567
• NM_017534.6:c.1975-47A>G

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.1975-47A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0574 in 1,481,808 control chromosomes in the GnomAD database, including 2,791 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.054 (249 hom., cov: 32)
  • Exomes 𝑓: 0.058 (2542 hom.)
• Consequence: MYH2 NM_017534.6 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.136
• Publications: 2 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=-0.82).
• BP6: Variant 17-10535412-T-C is Benign according to our data. Variant chr17-10535412-T-C is described in ClinVar as Benign. ClinVar VariationId is 260815.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.114 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_017534.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MYH2	NM_017534.6	MANE Select	c.1975-47A>G		intron	N/A	NP_060004.3
	MYH2	NM_001100112.2		c.1975-47A>G		intron	N/A	NP_001093582.1
	MYHAS	NR_125367.1		n.168-32125T>C		intron	N/A

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MYH2	ENST00000245503.10	TSL:1 MANE Select	c.1975-47A>G		intron	N/A	ENSP00000245503.5
	MYH2	ENST00000532183.6	TSL:1	c.1974+1118A>G		intron	N/A	ENSP00000433944.1
	MYH2	ENST00000622564.4	TSL:1	c.1974+1118A>G		intron	N/A	ENSP00000482463.1

Frequencies

GnomAD3 genomes AF: 0.0537 AC: 8167 AN: 152132 Hom.: 246 Cov.: 32

Gnomad AFR AF: 0.0454

Gnomad AMI AF: 0.0581

Gnomad AMR AF: 0.0433

Gnomad ASJ AF: 0.0804

Gnomad EAS AF: 0.0291

Gnomad SAS AF: 0.122

Gnomad FIN AF: 0.0526

Gnomad MID AF: 0.0728

Gnomad NFE AF: 0.0564

Gnomad OTH AF: 0.0670

GnomAD2 exomes AF: 0.0576 AC: 13829 AN: 240158 AF XY: 0.0614

Gnomad AFR exome AF: 0.0459

Gnomad AMR exome AF: 0.0354

Gnomad ASJ exome AF: 0.0828

Gnomad EAS exome AF: 0.0228

Gnomad FIN exome AF: 0.0542

Gnomad NFE exome AF: 0.0552

Gnomad OTH exome AF: 0.0552

GnomAD4 exome AF: 0.0578 AC: 76862 AN: 1329558 Hom.: 2542 Cov.: 21 AF XY: 0.0597 AC XY: 39871 AN XY: 667994

African (AFR) AF: 0.0484 AC: 1486 AN: 30684

American (AMR) AF: 0.0361 AC: 1580 AN: 43780

Ashkenazi Jewish (ASJ) AF: 0.0830 AC: 2097 AN: 25276

East Asian (EAS) AF: 0.0286 AC: 1113 AN: 38906

South Asian (SAS) AF: 0.110 AC: 9148 AN: 83124

European-Finnish (FIN) AF: 0.0536 AC: 2843 AN: 53066

Middle Eastern (MID) AF: 0.0576 AC: 316 AN: 5484

European-Non Finnish (NFE) AF: 0.0553 AC: 54894 AN: 993288

Other (OTH) AF: 0.0605 AC: 3385 AN: 55950

GnomAD4 genome AF: 0.0537 AC: 8183 AN: 152250 Hom.: 249 Cov.: 32 AF XY: 0.0552 AC XY: 4106 AN XY: 74438

African (AFR) AF: 0.0456 AC: 1894 AN: 41544

American (AMR) AF: 0.0432 AC: 661 AN: 15302

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

East Asian (EAS) AF: 0.0291 AC: 151 AN: 5182

South Asian (SAS) AF: 0.122 AC: 590 AN: 4820

European-Finnish (FIN) AF: 0.0526 AC: 558 AN: 10604

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

European-Non Finnish (NFE) AF: 0.0564 AC: 3836 AN: 68008

Other (OTH) AF: 0.0658 AC: 139 AN: 2112

Alfa AF: 0.0528 Hom.: 65

Bravo AF: 0.0507

Asia WGS AF: 0.0730 AC: 254 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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

not specified Benign:1

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	1.4
DANN	Benign	0.61
PhyloP100		-0.14
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs3744567; hg19: chr17-10438729;