17-10540007-C-T

Variant names:

• chr17-10540007-C-T
• rs116419997
• NM_017534.6:c.1068G>A

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Moderate BP6 BP7

The NM_017534.6(MYH2):​c.1068G>A​(p.Thr356Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000477 in 1,614,028 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. T356T) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000053 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000047 (0 hom.)
• Consequence: MYH2 NM_017534.6 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: -0.615
• 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: Likely_benign. The variant received -4 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.26).
• BP6: Variant 17-10540007-C-T is Benign according to our data. Variant chr17-10540007-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 321693.
• BP7: Synonymous conserved (PhyloP=-0.615 with no splicing effect.

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.1068G>A	p.Thr356Thr	synonymous	Exon 12 of 40	NP_060004.3
	MYH2	NM_001100112.2		c.1068G>A	p.Thr356Thr	synonymous	Exon 12 of 40	NP_001093582.1	Q9UKX2-1
	MYHAS	NR_125367.1		n.168-27530C>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.1068G>A	p.Thr356Thr	synonymous	Exon 12 of 40	ENSP00000245503.5	Q9UKX2-1
	MYH2	ENST00000532183.6	TSL:1	c.1068G>A	p.Thr356Thr	synonymous	Exon 11 of 17	ENSP00000433944.1	Q9UKX2-2
	MYH2	ENST00000622564.4	TSL:1	c.1068G>A	p.Thr356Thr	synonymous	Exon 12 of 18	ENSP00000482463.1	Q9UKX2-2

Frequencies

GnomAD3 genomes AF: 0.0000460 AC: 7 AN: 152072 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000966

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000386

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000875 AC: 22 AN: 251386 AF XY: 0.0000957

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.0000578

Gnomad ASJ exome AF: 0.0000992

Gnomad EAS exome AF: 0.000598

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000440

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.0000472 AC: 69 AN: 1461838 Hom.: 0 Cov.: 32 AF XY: 0.0000564 AC XY: 41 AN XY: 727222

African (AFR) AF: 0.0000299 AC: 1 AN: 33480

American (AMR) AF: 0.0000671 AC: 3 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0000383 AC: 1 AN: 26134

East Asian (EAS) AF: 0.000353 AC: 14 AN: 39696

South Asian (SAS) AF: 0.0000464 AC: 4 AN: 86256

European-Finnish (FIN) AF: 0.0000374 AC: 2 AN: 53420

Middle Eastern (MID) AF: 0.000347 AC: 2 AN: 5768

European-Non Finnish (NFE) AF: 0.0000324 AC: 36 AN: 1111966

Other (OTH) AF: 0.0000993 AC: 6 AN: 60394

GnomAD4 genome AF: 0.0000526 AC: 8 AN: 152190 Hom.: 0 Cov.: 32 AF XY: 0.0000672 AC XY: 5 AN XY: 74394

African (AFR) AF: 0.000120 AC: 5 AN: 41526

American (AMR) AF: 0.00 AC: 0 AN: 15278

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

East Asian (EAS) AF: 0.000387 AC: 2 AN: 5166

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10596

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

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68008

Other (OTH) AF: 0.00 AC: 0 AN: 2114

Alfa AF: 0.0000435 Hom.: 0

Bravo AF: 0.0000491

EpiCase AF: 0.000164

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	-	Inclusion Body Myopathy, Dominant (1)
-	-	1	Myopathy, proximal, and ophthalmoplegia (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.26
CADD	Benign	12
DANN	Benign	0.79
PhyloP100		-0.61

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs116419997; hg19: chr17-10443324; COSMIC: COSV107308478; COSMIC: COSV107308478;