17-10539660-T-C

Variant names:

• chr17-10539660-T-C
• rs2277653
• NM_017534.6:c.1148-98A>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.1148-98A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.436 in 1,319,806 control chromosomes in the GnomAD database, including 132,189 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.42 (14261 hom., cov: 32)
  • Exomes 𝑓: 0.44 (117928 hom.)
• Consequence: MYH2 NM_017534.6 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.354
• Publications: 4 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=-0.85).
• BP6: Variant 17-10539660-T-C is Benign according to our data. Variant chr17-10539660-T-C is described in ClinVar as Benign. ClinVar VariationId is 1175449.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.829 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYH2	NM_017534.6	c.1148-98A>G		intron_variant	Intron 12 of 39	ENST00000245503.10	NP_060004.3
MYH2	NM_001100112.2	c.1148-98A>G		intron_variant	Intron 12 of 39		NP_001093582.1
MYHAS	NR_125367.1	n.168-27877T>C		intron_variant	Intron 2 of 10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MYH2	ENST00000245503.10	c.1148-98A>G		intron_variant	Intron 12 of 39	1	NM_017534.6	ENSP00000245503.5

Frequencies

GnomAD3 genomes AF: 0.420 AC: 63748 AN: 151896 Hom.: 14243 Cov.: 32

Gnomad AFR AF: 0.332

Gnomad AMI AF: 0.455

Gnomad AMR AF: 0.492

Gnomad ASJ AF: 0.448

Gnomad EAS AF: 0.851

Gnomad SAS AF: 0.618

Gnomad FIN AF: 0.450

Gnomad MID AF: 0.443

Gnomad NFE AF: 0.403

Gnomad OTH AF: 0.416

GnomAD4 exome AF: 0.439 AC: 512271 AN: 1167792 Hom.: 117928 AF XY: 0.443 AC XY: 262252 AN XY: 592050

African (AFR) AF: 0.330 AC: 8920 AN: 27020

American (AMR) AF: 0.586 AC: 23628 AN: 40320

Ashkenazi Jewish (ASJ) AF: 0.453 AC: 10933 AN: 24154

East Asian (EAS) AF: 0.839 AC: 31306 AN: 37312

South Asian (SAS) AF: 0.596 AC: 46708 AN: 78394

European-Finnish (FIN) AF: 0.438 AC: 21927 AN: 50012

Middle Eastern (MID) AF: 0.455 AC: 2408 AN: 5296

European-Non Finnish (NFE) AF: 0.403 AC: 344026 AN: 854634

Other (OTH) AF: 0.443 AC: 22415 AN: 50650

GnomAD4 genome AF: 0.420 AC: 63811 AN: 152014 Hom.: 14261 Cov.: 32 AF XY: 0.431 AC XY: 32041 AN XY: 74274

African (AFR) AF: 0.332 AC: 13778 AN: 41470

American (AMR) AF: 0.492 AC: 7515 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.448 AC: 1555 AN: 3470

East Asian (EAS) AF: 0.850 AC: 4390 AN: 5162

South Asian (SAS) AF: 0.618 AC: 2981 AN: 4824

European-Finnish (FIN) AF: 0.450 AC: 4736 AN: 10516

Middle Eastern (MID) AF: 0.446 AC: 131 AN: 294

European-Non Finnish (NFE) AF: 0.404 AC: 27433 AN: 67986

Other (OTH) AF: 0.416 AC: 877 AN: 2110

Alfa AF: 0.402 Hom.: 2024

Bravo AF: 0.418

Asia WGS AF: 0.671 AC: 2331 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jul 15, 2018

GeneDx

Significance: 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	-0.85
CADD	Benign	3.5
DANN	Benign	0.50
PhyloP100		0.35
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: rs2277653; hg19: chr17-10442977; COSMIC: COSV107308715; COSMIC: COSV107308715;