rs121918280
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1PM2PM5PP3_StrongPP5_Very_Strong
The NM_207122.2(EXT2):c.679G>A(p.Asp227Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000031 in 1,613,984 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 13/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D227G) has been classified as Pathogenic.
Frequency
Consequence
NM_207122.2 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 18 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
EXT2 | NM_207122.2 | c.679G>A | p.Asp227Asn | missense_variant | 4/14 | ENST00000533608.7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
EXT2 | ENST00000533608.7 | c.679G>A | p.Asp227Asn | missense_variant | 4/14 | 1 | NM_207122.2 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000131 AC: 2AN: 152146Hom.: 0 Cov.: 32
GnomAD4 exome AF: 0.00000205 AC: 3AN: 1461838Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1AN XY: 727220
GnomAD4 genome ? AF: 0.0000131 AC: 2AN: 152146Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74304
ClinVar
Submissions by phenotype
Exostoses, multiple, type 2 Pathogenic:2
Pathogenic, no assertion criteria provided | literature only | OMIM | May 01, 2009 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Nov 27, 2023 | This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 227 of the EXT2 protein (p.Asp227Asn). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with hereditary multiple osteochondromatosis and multiple osteochondromas (PMID: 9326317, 10713884, 10750558, 11432960, 16283885, 17041877). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 2474). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt EXT2 protein function with a positive predictive value of 80%. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on EXT2 function (PMID: 9326317, 10750558). For these reasons, this variant has been classified as Pathogenic. - |
Exostoses, multiple, type 2;C4225248:Seizures-scoliosis-macrocephaly syndrome Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Aug 18, 2021 | - - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Oct 01, 2018 | - - |
Seizures-scoliosis-macrocephaly syndrome Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | May 01, 2009 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at