17-10543191-T-G

Variant names:

• chr17-10543191-T-G
• rs11078849
• NM_017534.6:c.742-30A>C

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.742-30A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.437 in 1,494,622 control chromosomes in the GnomAD database, including 149,814 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.42 (14265 hom., cov: 33)
  • Exomes 𝑓: 0.44 (135549 hom.)
• Consequence: MYH2 NM_017534.6 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.761
• Publications: 5 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 17-10543191-T-G is Benign according to our data. Variant chr17-10543191-T-G is described in ClinVar as Benign. ClinVar VariationId is 260828.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.828 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYH2	NM_017534.6	c.742-30A>C		intron_variant	Intron 8 of 39	ENST00000245503.10	NP_060004.3
MYH2	NM_001100112.2	c.742-30A>C		intron_variant	Intron 8 of 39		NP_001093582.1
MYHAS	NR_125367.1	n.168-24346T>G		intron_variant	Intron 2 of 10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MYH2	ENST00000245503.10	c.742-30A>C		intron_variant	Intron 8 of 39	1	NM_017534.6	ENSP00000245503.5

Frequencies

GnomAD3 genomes AF: 0.420 AC: 63776 AN: 151938 Hom.: 14247 Cov.: 33

Gnomad AFR AF: 0.332

Gnomad AMI AF: 0.454

Gnomad AMR AF: 0.492

Gnomad ASJ AF: 0.448

Gnomad EAS AF: 0.850

Gnomad SAS AF: 0.619

Gnomad FIN AF: 0.452

Gnomad MID AF: 0.443

Gnomad NFE AF: 0.403

Gnomad OTH AF: 0.415

GnomAD2 exomes AF: 0.498 AC: 118309 AN: 237796 AF XY: 0.495

Gnomad AFR exome AF: 0.335

Gnomad AMR exome AF: 0.619

Gnomad ASJ exome AF: 0.461

Gnomad EAS exome AF: 0.870

Gnomad FIN exome AF: 0.451

Gnomad NFE exome AF: 0.409

Gnomad OTH exome AF: 0.457

GnomAD4 exome AF: 0.439 AC: 589729 AN: 1342566 Hom.: 135549 Cov.: 21 AF XY: 0.442 AC XY: 297690 AN XY: 672814

African (AFR) AF: 0.334 AC: 10054 AN: 30134

American (AMR) AF: 0.599 AC: 25174 AN: 42018

Ashkenazi Jewish (ASJ) AF: 0.456 AC: 11370 AN: 24908

East Asian (EAS) AF: 0.841 AC: 32844 AN: 39076

South Asian (SAS) AF: 0.604 AC: 47966 AN: 79432

European-Finnish (FIN) AF: 0.440 AC: 23221 AN: 52806

Middle Eastern (MID) AF: 0.477 AC: 2111 AN: 4426

European-Non Finnish (NFE) AF: 0.406 AC: 411996 AN: 1013696

Other (OTH) AF: 0.446 AC: 24993 AN: 56070

GnomAD4 genome AF: 0.420 AC: 63839 AN: 152056 Hom.: 14265 Cov.: 33 AF XY: 0.432 AC XY: 32095 AN XY: 74336

African (AFR) AF: 0.333 AC: 13799 AN: 41486

American (AMR) AF: 0.492 AC: 7520 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.448 AC: 1556 AN: 3472

East Asian (EAS) AF: 0.849 AC: 4384 AN: 5162

South Asian (SAS) AF: 0.618 AC: 2975 AN: 4814

European-Finnish (FIN) AF: 0.452 AC: 4765 AN: 10552

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

European-Non Finnish (NFE) AF: 0.403 AC: 27418 AN: 67972

Other (OTH) AF: 0.415 AC: 878 AN: 2116

Alfa AF: 0.402 Hom.: 5649

Bravo AF: 0.418

Asia WGS AF: 0.671 AC: 2314 AN: 3454

ClinVar

Significance: Benign

Submissions summary: Benign:4

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

- -

Myopathy, proximal, and ophthalmoplegia Benign:1

Sep 05, 2021

Genome-Nilou Lab

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	-0.82
CADD	Benign	1.5
DANN	Benign	0.84
PhyloP100		-0.76
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: rs11078849; hg19: chr17-10446508; COSMIC: COSV55434345; COSMIC: COSV55434345;