17-10548996-A-G

Variant names:

• chr17-10548996-A-G
• rs3760431
• NM_017534.6:c.-21+379T>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_017534.6(MYH2):​c.-21+379T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.417 in 152,096 control chromosomes in the GnomAD database, including 14,161 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.42 (14161 hom., cov: 33)
• Consequence: MYH2 NM_017534.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.69
• Publications: 1 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.83 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYH2	NM_017534.6	c.-21+379T>C		intron_variant	Intron 2 of 39	ENST00000245503.10	NP_060004.3
MYH2	NM_001100112.2	c.-21+379T>C		intron_variant	Intron 2 of 39		NP_001093582.1
MYHAS	NR_125367.1	n.168-18541A>G		intron_variant	Intron 2 of 10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MYH2	ENST00000245503.10	c.-21+379T>C		intron_variant	Intron 2 of 39	1	NM_017534.6	ENSP00000245503.5

Frequencies

GnomAD3 genomes AF: 0.417 AC: 63410 AN: 151978 Hom.: 14144 Cov.: 33

Gnomad AFR AF: 0.323

Gnomad AMI AF: 0.455

Gnomad AMR AF: 0.491

Gnomad ASJ AF: 0.448

Gnomad EAS AF: 0.851

Gnomad SAS AF: 0.618

Gnomad FIN AF: 0.452

Gnomad MID AF: 0.443

Gnomad NFE AF: 0.403

Gnomad OTH AF: 0.413

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.417 AC: 63472 AN: 152096 Hom.: 14161 Cov.: 33 AF XY: 0.429 AC XY: 31910 AN XY: 74342

African (AFR) AF: 0.323 AC: 13417 AN: 41494

American (AMR) AF: 0.492 AC: 7509 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.448 AC: 1554 AN: 3470

East Asian (EAS) AF: 0.851 AC: 4410 AN: 5184

South Asian (SAS) AF: 0.618 AC: 2983 AN: 4828

European-Finnish (FIN) AF: 0.452 AC: 4768 AN: 10554

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

European-Non Finnish (NFE) AF: 0.403 AC: 27412 AN: 67974

Other (OTH) AF: 0.413 AC: 874 AN: 2114

Alfa AF: 0.410 Hom.: 16484

Bravo AF: 0.415

Asia WGS AF: 0.669 AC: 2324 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	11
DANN	Benign	0.76
PhyloP100		1.7
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: rs3760431; hg19: chr17-10452313; COSMIC: COSV55434408; COSMIC: COSV55434408;