rs3744565

Variant names:

• chr17-10531608-T-C
• rs3744565
• NM_017534.6:c.2697+25A>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.2697+25A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.428 in 1,613,758 control chromosomes in the GnomAD database, including 155,812 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.41 (13792 hom., cov: 32)
  • Exomes 𝑓: 0.43 (142020 hom.)
• Consequence: MYH2 NM_017534.6 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.280
• Publications: 8 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=-0.89).
• BP6: Variant 17-10531608-T-C is Benign according to our data. Variant chr17-10531608-T-C is described in ClinVar as Benign. ClinVar VariationId is 260818.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.813 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MYH2	NM_017534.6	MANE Select	c.2697+25A>G		intron	N/A	NP_060004.3
	MYH2	NM_001100112.2		c.2697+25A>G		intron	N/A	NP_001093582.1
	MYHAS	NR_125367.1		n.168-35929T>C		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MYH2	ENST00000245503.10	TSL:1 MANE Select	c.2697+25A>G		intron	N/A	ENSP00000245503.5
	MYH2	ENST00000532183.6	TSL:1	c.1974+4922A>G		intron	N/A	ENSP00000433944.1
	MYH2	ENST00000622564.4	TSL:1	c.1974+4922A>G		intron	N/A	ENSP00000482463.1

Frequencies

GnomAD3 genomes AF: 0.411 AC: 62519 AN: 151952 Hom.: 13781 Cov.: 32

Gnomad AFR AF: 0.306

Gnomad AMI AF: 0.455

Gnomad AMR AF: 0.487

Gnomad ASJ AF: 0.448

Gnomad EAS AF: 0.834

Gnomad SAS AF: 0.616

Gnomad FIN AF: 0.451

Gnomad MID AF: 0.443

Gnomad NFE AF: 0.403

Gnomad OTH AF: 0.408

GnomAD2 exomes AF: 0.487 AC: 121864 AN: 250400 AF XY: 0.486

Gnomad AFR exome AF: 0.302

Gnomad AMR exome AF: 0.599

Gnomad ASJ exome AF: 0.452

Gnomad EAS exome AF: 0.849

Gnomad FIN exome AF: 0.447

Gnomad NFE exome AF: 0.403

Gnomad OTH exome AF: 0.443

GnomAD4 exome AF: 0.430 AC: 628817 AN: 1461688 Hom.: 142020 Cov.: 50 AF XY: 0.434 AC XY: 315863 AN XY: 727156

African (AFR) AF: 0.300 AC: 10057 AN: 33478

American (AMR) AF: 0.583 AC: 26063 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.453 AC: 11829 AN: 26134

East Asian (EAS) AF: 0.831 AC: 32972 AN: 39696

South Asian (SAS) AF: 0.594 AC: 51258 AN: 86254

European-Finnish (FIN) AF: 0.438 AC: 23388 AN: 53418

Middle Eastern (MID) AF: 0.456 AC: 2627 AN: 5766

European-Non Finnish (NFE) AF: 0.400 AC: 444244 AN: 1111838

Other (OTH) AF: 0.437 AC: 26379 AN: 60380

GnomAD4 genome AF: 0.411 AC: 62564 AN: 152070 Hom.: 13792 Cov.: 32 AF XY: 0.424 AC XY: 31487 AN XY: 74344

African (AFR) AF: 0.306 AC: 12693 AN: 41464

American (AMR) AF: 0.488 AC: 7447 AN: 15274

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

East Asian (EAS) AF: 0.834 AC: 4306 AN: 5164

South Asian (SAS) AF: 0.615 AC: 2965 AN: 4818

European-Finnish (FIN) AF: 0.451 AC: 4775 AN: 10584

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

European-Non Finnish (NFE) AF: 0.403 AC: 27415 AN: 67972

Other (OTH) AF: 0.407 AC: 861 AN: 2116

Alfa AF: 0.410 Hom.: 17161

Bravo AF: 0.408

Asia WGS AF: 0.653 AC: 2267 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Myopathy, proximal, and ophthalmoplegia (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	6.0
DANN	Benign	0.41
PhyloP100		-0.28
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.12		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: rs3744565; hg19: chr17-10434925; COSMIC: COSV55434331;