chr17-10525735-G-A

Variant names:

• chr17-10525735-G-A
• rs61739663
• NM_017534.6:c.4329C>T

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.4329C>T​(p.Ala1443Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00601 in 1,614,174 control chromosomes in the GnomAD database, including 39 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0045 (2 hom., cov: 33)
  • Exomes 𝑓: 0.0062 (37 hom.)
• Consequence: MYH2 NM_017534.6 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -1.18
• Publications: 3 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=-0.81).
• BP6: Variant 17-10525735-G-A is Benign according to our data. Variant chr17-10525735-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 465941.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.18 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00452 (688/152286) while in subpopulation NFE AF = 0.00623 (424/68024). AF 95% confidence interval is 0.00574. There are 2 homozygotes in GnomAd4. There are 319 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 2 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.4329C>T	p.Ala1443Ala	synonymous	Exon 31 of 40	NP_060004.3
	MYH2	NM_001100112.2		c.4329C>T	p.Ala1443Ala	synonymous	Exon 31 of 40	NP_001093582.1
	MYHAS	NR_125367.1		n.168-41802G>A		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MYH2	ENST00000245503.10	TSL:1 MANE Select	c.4329C>T	p.Ala1443Ala	synonymous	Exon 31 of 40	ENSP00000245503.5
	MYH2	ENST00000532183.6	TSL:1	c.1975-4303C>T		intron	N/A	ENSP00000433944.1
	MYH2	ENST00000622564.4	TSL:1	c.1975-4303C>T		intron	N/A	ENSP00000482463.1

Frequencies

GnomAD3 genomes AF: 0.00453 AC: 690 AN: 152168 Hom.: 2 Cov.: 33

Gnomad AFR AF: 0.00386

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00524

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000377

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.00626

Gnomad OTH AF: 0.00813

GnomAD2 exomes AF: 0.00377 AC: 948 AN: 251408 AF XY: 0.00381

Gnomad AFR exome AF: 0.00338

Gnomad AMR exome AF: 0.00257

Gnomad ASJ exome AF: 0.0000992

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000970

Gnomad NFE exome AF: 0.00669

Gnomad OTH exome AF: 0.00343

GnomAD4 exome AF: 0.00616 AC: 9012 AN: 1461888 Hom.: 37 Cov.: 33 AF XY: 0.00582 AC XY: 4231 AN XY: 727242

African (AFR) AF: 0.00293 AC: 98 AN: 33480

American (AMR) AF: 0.00259 AC: 116 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0000765 AC: 2 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00155 AC: 83 AN: 53420

Middle Eastern (MID) AF: 0.00139 AC: 8 AN: 5768

European-Non Finnish (NFE) AF: 0.00751 AC: 8354 AN: 1112006

Other (OTH) AF: 0.00581 AC: 351 AN: 60396

GnomAD4 genome AF: 0.00452 AC: 688 AN: 152286 Hom.: 2 Cov.: 33 AF XY: 0.00428 AC XY: 319 AN XY: 74464

African (AFR) AF: 0.00385 AC: 160 AN: 41558

American (AMR) AF: 0.00523 AC: 80 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5178

South Asian (SAS) AF: 0.00 AC: 0 AN: 4822

European-Finnish (FIN) AF: 0.000377 AC: 4 AN: 10614

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.00623 AC: 424 AN: 68024

Other (OTH) AF: 0.00804 AC: 17 AN: 2114

Alfa AF: 0.00515 Hom.: 4

Bravo AF: 0.00495

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00545

EpiControl AF: 0.00528

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	MYH2-related disorder (1)
-	-	1	Myopathy, proximal, and ophthalmoplegia (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	0.086
DANN	Benign	0.88
PhyloP100		-1.2
Mutation Taster		=96/4	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: rs61739663; hg19: chr17-10429052;