rs886041199
Variant names:
Variant summary
Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_000401.3(EXT2):c.1005_1006dupGC(p.His336ArgfsTer30) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,308 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: not found (cov: 32)
Exomes 𝑓: 0.0000014 ( 0 hom. )
Consequence
EXT2
NM_000401.3 frameshift
NM_000401.3 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 1.32
Publications
1 publications found
Genes affected
EXT2 (HGNC:3513): (exostosin glycosyltransferase 2) This gene encodes one of two glycosyltransferases involved in the chain elongation step of heparan sulfate biosynthesis. Mutations in this gene cause the type II form of multiple exostoses. Alternatively spliced transcript variants encoding different isoforms have been noted for this gene. [provided by RefSeq, Jul 2008]
EXT2 Gene-Disease associations (from GenCC):
- exostoses, multiple, type 2Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), ClinGen, Ambry Genetics, G2P
- seizures-scoliosis-macrocephaly syndromeInheritance: AR Classification: STRONG, SUPPORTIVE, LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), Orphanet
- hereditary multiple osteochondromasInheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
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ACMG classification
Classification was made for transcript
Our verdict: Pathogenic. The variant received 18 ACMG points.
PVS1
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 11-44124950-A-AGC is Pathogenic according to our data. Variant chr11-44124950-A-AGC is described in ClinVar as Pathogenic. ClinVar VariationId is 279805.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Variant Effect in Transcripts
ACMG analysis was done for transcript: NM_000401.3. 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 |
|---|---|---|---|---|---|---|---|---|---|
| EXT2 | NM_207122.2 | MANE Select | c.906_907dupGC | p.His303ArgfsTer30 | frameshift | Exon 5 of 14 | NP_997005.1 | ||
| EXT2 | NM_000401.3 | c.1005_1006dupGC | p.His336ArgfsTer30 | frameshift | Exon 5 of 14 | NP_000392.3 | |||
| EXT2 | NM_001178083.3 | c.906_907dupGC | p.His303ArgfsTer30 | frameshift | Exon 5 of 15 | NP_001171554.1 |
Ensembl Transcripts
| Sel. | Gene | Transcript | Tags | HGVSc | HGVSp | Effect | Exon Rank | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|---|
| EXT2 | ENST00000533608.7 | TSL:1 MANE Select | c.906_907dupGC | p.His303ArgfsTer30 | frameshift | Exon 5 of 14 | ENSP00000431173.2 | ||
| EXT2 | ENST00000358681.8 | TSL:1 | c.906_907dupGC | p.His303ArgfsTer30 | frameshift | Exon 5 of 15 | ENSP00000351509.4 | ||
| EXT2 | ENST00000343631.4 | TSL:1 | c.906_907dupGC | p.His303ArgfsTer30 | frameshift | Exon 6 of 15 | ENSP00000342656.3 |
Frequencies
GnomAD3 genomes
GnomAD3 genomes
Cov.:
32
GnomAD4 exome AF: 0.00000137 AC: 2AN: 1461308Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1AN XY: 726968 show subpopulations
GnomAD4 exome
AF:
AC:
2
AN:
1461308
Hom.:
Cov.:
32
AF XY:
AC XY:
1
AN XY:
726968
show subpopulations
African (AFR)
AF:
AC:
0
AN:
33462
American (AMR)
AF:
AC:
2
AN:
44724
Ashkenazi Jewish (ASJ)
AF:
AC:
0
AN:
26136
East Asian (EAS)
AF:
AC:
0
AN:
39700
South Asian (SAS)
AF:
AC:
0
AN:
86230
European-Finnish (FIN)
AF:
AC:
0
AN:
53406
Middle Eastern (MID)
AF:
AC:
0
AN:
5304
European-Non Finnish (NFE)
AF:
AC:
0
AN:
1112004
Other (OTH)
AF:
AC:
0
AN:
60342
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.500
Heterozygous variant carriers
0
0
1
1
2
2
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance
GnomAD4 genome
GnomAD4 genome
Cov.:
32
ClinVar
ClinVar submissions as Germline
View on ClinVar Significance:Pathogenic
Revision:criteria provided, multiple submitters, no conflicts
Pathogenic
VUS
Benign
Condition
1
-
-
Exostoses, multiple, type 2 (1)
1
-
-
Exostoses, multiple, type 2;C4225248:Seizures-scoliosis-macrocephaly syndrome (1)
1
-
-
not provided (1)
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
PhyloP100
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at
Publications
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