dbSNP rs35455466: EXT2:p.His88Gln (chr11-44107976-C-A) – ACMG Classification: Uncertain_significance (4 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_207122.2(EXT2):c.264C>A(p.His88Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. H88H) has been classified as Benign.

Frequency

Genomes: not found (cov: 32)

Consequence

EXT2
NM_207122.2 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.36

Publications

0 publications found

Variant links:

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 2
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P, Genomics England PanelApp, ClinGen, Ambry Genetics
seizures-scoliosis-macrocephaly syndrome
Inheritance: AR Classification: STRONG, SUPPORTIVE, LIMITED Submitted by: Orphanet, Ambry Genetics, Labcorp Genetics (formerly Invitae)
hereditary multiple osteochondromas
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

EXT2 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.9

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_207122.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
EXT2	NM_207122.2	MANE Select	c.264C>A	p.His88Gln	missense	Exon 2 of 14	NP_997005.1	Q93063-1
EXT2	NM_000401.3		c.363C>A	p.His121Gln	missense	Exon 2 of 14	NP_000392.3	Q93063-3
EXT2	NM_001178083.3		c.264C>A	p.His88Gln	missense	Exon 2 of 15	NP_001171554.1	Q93063-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
EXT2	ENST00000533608.7	TSL:1 MANE Select	c.264C>A	p.His88Gln	missense	Exon 2 of 14	ENSP00000431173.2	Q93063-1
EXT2	ENST00000358681.8	TSL:1	c.264C>A	p.His88Gln	missense	Exon 2 of 15	ENSP00000351509.4	Q93063-2
EXT2	ENST00000343631.4	TSL:1	c.264C>A	p.His88Gln	missense	Exon 3 of 15	ENSP00000342656.3	Q93063-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.86

BayesDel_addAF

Pathogenic

0.41

BayesDel_noAF

Pathogenic

0.36

CADD

Benign

(source)

DANN

Uncertain

0.98

DEOGEN2

Uncertain

0.43

Eigen

Benign

0.10

Eigen_PC

Benign

0.077

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Uncertain

0.94

M_CAP

Benign

0.080

MetaRNN

Pathogenic

0.90

MetaSVM

Uncertain

0.37

MutationAssessor

Uncertain

2.0

PhyloP100

1.4

PrimateAI

Pathogenic

0.86

PROVEAN

Uncertain

-2.7

REVEL

Pathogenic

0.69

Sift

Benign

0.26

Sift4G

Benign

0.28

Polyphen

0.99

Vest4

0.85

MutPred

0.80

Loss of catalytic residue at H88 (P = 0.0541)

MVP

0.99

MPC

0.80

ClinPred

0.93

GERP RS

0.16

Varity_R

0.28

gMVP

0.76

Mutation Taster

=22/78

disease causing

(source)

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over