17-10547738-C-T

Variant names:

• chr17-10547738-C-T
• rs142539913
• NM_017534.6:c.183G>A

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_017534.6(MYH2):​c.183G>A​(p.Thr61Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0101 in 1,614,188 control chromosomes in the GnomAD database, including 113 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0071 (6 hom., cov: 32)
  • Exomes 𝑓: 0.010 (107 hom.)
• Consequence: MYH2 NM_017534.6 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -5.89
• Publications: 6 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.75).
• BP6: Variant 17-10547738-C-T is Benign according to our data. Variant chr17-10547738-C-T is described in ClinVar as Benign. ClinVar VariationId is 465923.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-5.89 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00711 (1083/152306) while in subpopulation NFE AF = 0.0118 (802/68014). AF 95% confidence interval is 0.0111. There are 6 homozygotes in GnomAd4. There are 509 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 6 SD,AR,AD gene

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.183G>A	p.Thr61Thr	synonymous	Exon 3 of 40	NP_060004.3
	MYH2	NM_001100112.2		c.183G>A	p.Thr61Thr	synonymous	Exon 3 of 40	NP_001093582.1	Q9UKX2-1
	MYHAS	NR_125367.1		n.168-19799C>T		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MYH2	ENST00000245503.10	TSL:1 MANE Select	c.183G>A	p.Thr61Thr	synonymous	Exon 3 of 40	ENSP00000245503.5	Q9UKX2-1
	MYH2	ENST00000532183.6	TSL:1	c.183G>A	p.Thr61Thr	synonymous	Exon 2 of 17	ENSP00000433944.1	Q9UKX2-2
	MYH2	ENST00000622564.4	TSL:1	c.183G>A	p.Thr61Thr	synonymous	Exon 3 of 18	ENSP00000482463.1	Q9UKX2-2

Frequencies

GnomAD3 genomes AF: 0.00712 AC: 1083 AN: 152188 Hom.: 6 Cov.: 32

Gnomad AFR AF: 0.00181

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.00602

Gnomad ASJ AF: 0.00461

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00124

Gnomad FIN AF: 0.00772

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0118

Gnomad OTH AF: 0.00430

GnomAD2 exomes AF: 0.00767 AC: 1928 AN: 251408 AF XY: 0.00755

Gnomad AFR exome AF: 0.00141

Gnomad AMR exome AF: 0.00353

Gnomad ASJ exome AF: 0.00546

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00855

Gnomad NFE exome AF: 0.0127

Gnomad OTH exome AF: 0.00847

GnomAD4 exome AF: 0.0104 AC: 15168 AN: 1461882 Hom.: 107 Cov.: 34 AF XY: 0.0101 AC XY: 7318 AN XY: 727246

African (AFR) AF: 0.00149 AC: 50 AN: 33478

American (AMR) AF: 0.00427 AC: 191 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00566 AC: 148 AN: 26136

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39700

South Asian (SAS) AF: 0.00201 AC: 173 AN: 86258

European-Finnish (FIN) AF: 0.00852 AC: 455 AN: 53420

Middle Eastern (MID) AF: 0.000520 AC: 3 AN: 5768

European-Non Finnish (NFE) AF: 0.0123 AC: 13626 AN: 1112004

Other (OTH) AF: 0.00863 AC: 521 AN: 60396

GnomAD4 genome AF: 0.00711 AC: 1083 AN: 152306 Hom.: 6 Cov.: 32 AF XY: 0.00683 AC XY: 509 AN XY: 74490

African (AFR) AF: 0.00180 AC: 75 AN: 41568

American (AMR) AF: 0.00601 AC: 92 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.00461 AC: 16 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.00124 AC: 6 AN: 4824

European-Finnish (FIN) AF: 0.00772 AC: 82 AN: 10624

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0118 AC: 802 AN: 68014

Other (OTH) AF: 0.00425 AC: 9 AN: 2116

Alfa AF: 0.00840 Hom.: 1

Bravo AF: 0.00634

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.00862

EpiControl AF: 0.0106

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	-	2	Myopathy, proximal, and ophthalmoplegia (2)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.75
CADD	Benign	0.42
DANN	Benign	0.80
PhyloP100		-5.9
PromoterAI		-0.043	Neutral
Mutation Taster		=99/1	polymorphism

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: rs142539913; hg19: chr17-10451055;