chr17-10535367-T-C

Variant summary

Our verdict is Likely pathogenic. The variant received 9 ACMG points: 9P and 0B. PVS1PP5

The NM_017534.6(MYH2):​c.1975-2A>G variant causes a splice acceptor, intron change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000868 in 1,613,450 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (no stars).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0000082 ( 0 hom. )

Consequence

MYH2
NM_017534.6 splice_acceptor, intron

Scores

5
1
1
Splicing: ADA: 1.000
2

Clinical Significance

Pathogenic no assertion criteria provided P:1

Conservation

PhyloP100: 8.00

Publications

0 publications found
Variant links:
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]

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 9 ACMG points.

PVS1
Splicing +-2 bp (donor or acceptor) variant, LoF is a know mechanism of disease, Cryptic splice site detected, with MaxEntScore 5.9, offset of -35, new splice context is: ctgctcatatccatgtctAGagc. Cryptic site results in frameshift change. If cryptic site found is not functional and variant results in exon loss, it results in frameshift change.
PP5
Variant 17-10535367-T-C is Pathogenic according to our data. Variant chr17-10535367-T-C is described in ClinVar as [Pathogenic]. Clinvar id is 183663.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
MYH2NM_017534.6 linkc.1975-2A>G splice_acceptor_variant, intron_variant Intron 17 of 39 ENST00000245503.10 NP_060004.3 Q9UKX2-1
MYH2NM_001100112.2 linkc.1975-2A>G splice_acceptor_variant, intron_variant Intron 17 of 39 NP_001093582.1 Q9UKX2-1
MYHASNR_125367.1 linkn.168-32170T>C intron_variant Intron 2 of 10

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
MYH2ENST00000245503.10 linkc.1975-2A>G splice_acceptor_variant, intron_variant Intron 17 of 39 1 NM_017534.6 ENSP00000245503.5 Q9UKX2-1

Frequencies

GnomAD3 genomes
AF:
0.0000131
AC:
2
AN:
152200
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.000188
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.00
GnomAD2 exomes
AF:
0.0000239
AC:
6
AN:
250860
AF XY:
0.0000147
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.000231
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.000164
GnomAD4 exome
AF:
0.00000821
AC:
12
AN:
1461250
Hom.:
0
Cov.:
31
AF XY:
0.00000825
AC XY:
6
AN XY:
726976
show subpopulations
African (AFR)
AF:
0.00
AC:
0
AN:
33466
American (AMR)
AF:
0.00
AC:
0
AN:
44716
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
26130
East Asian (EAS)
AF:
0.00
AC:
0
AN:
39684
South Asian (SAS)
AF:
0.00
AC:
0
AN:
86228
European-Finnish (FIN)
AF:
0.000206
AC:
11
AN:
53402
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
5768
European-Non Finnish (NFE)
AF:
0.00
AC:
0
AN:
1111476
Other (OTH)
AF:
0.0000166
AC:
1
AN:
60380
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.500
Heterozygous variant carriers
0
1
2
4
5
6
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Variant carriers
0
2
4
6
8
10
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
GnomAD4 genome
AF:
0.0000131
AC:
2
AN:
152200
Hom.:
0
Cov.:
32
AF XY:
0.0000134
AC XY:
1
AN XY:
74352
show subpopulations
African (AFR)
AF:
0.00
AC:
0
AN:
41462
American (AMR)
AF:
0.00
AC:
0
AN:
15276
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
3472
East Asian (EAS)
AF:
0.00
AC:
0
AN:
5188
South Asian (SAS)
AF:
0.00
AC:
0
AN:
4828
European-Finnish (FIN)
AF:
0.000188
AC:
2
AN:
10614
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
316
European-Non Finnish (NFE)
AF:
0.00
AC:
0
AN:
68040
Other (OTH)
AF:
0.00
AC:
0
AN:
2092
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.525
Heterozygous variant carriers
0
0
1
1
2
2
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Genome Het
Variant carriers
0
2
4
6
8
10
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
Alfa
AF:
0.00
Hom.:
0
ExAC
AF:
0.0000165
AC:
2

ClinVar

Significance: Pathogenic
Submissions summary: Pathogenic:1
Revision: no assertion criteria provided
LINK: link

Submissions by phenotype

Myopathy, proximal, and ophthalmoplegia Pathogenic:1
May 01, 2010
OMIM
Significance:Pathogenic
Review Status:no assertion criteria provided
Collection Method:literature only

- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
0.63
D
BayesDel_noAF
Pathogenic
0.33
CADD
Pathogenic
30
DANN
Uncertain
0.99
Eigen
Pathogenic
1.1
Eigen_PC
Pathogenic
0.95
FATHMM_MKL
Pathogenic
0.98
D
PhyloP100
8.0
GERP RS
5.0
Mutation Taster
=0/100
disease causing (ClinVar)

Splicing

Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Pathogenic
1.0
dbscSNV1_RF
Pathogenic
0.93
SpliceAI score (max)
1.0
Details are displayed if max score is > 0.2
DS_AL_spliceai
1.0
Position offset: -2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

Other links and lift over

dbSNP: rs746770617; hg19: chr17-10438684; API