11-44096311-C-T

Variant names:

• chr11-44096311-C-T
• rs1225833538
• ENST00000343631.4:c.-41C>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The ENST00000343631.4(EXT2):​c.-41C>T variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: EXT2 ENST00000343631.4 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.396
• Publications: 0 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 2

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), ClinGen, Ambry Genetics, G2P
• seizures-scoliosis-macrocephaly syndrome

  Inheritance: AR Classification: STRONG, SUPPORTIVE, LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), Orphanet
• hereditary multiple osteochondromas

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.11341846).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EXT2	NM_207122.2	c.-31+459C>T		intron_variant	Intron 1 of 13	ENST00000533608.7	NP_997005.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
EXT2	ENST00000533608.7	c.-31+459C>T		intron_variant	Intron 1 of 13	1	NM_207122.2	ENSP00000431173.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.061	T
BayesDel_noAF	Benign	-0.32
CADD	Benign	9.6
DANN	Benign	0.97
Eigen	Benign	-0.51
Eigen_PC	Benign	-0.69
FATHMM_MKL	Benign	0.017	N
LIST_S2	Benign	0.53	T
M_CAP	Benign	0.048	D
MetaRNN	Benign	0.11	T
MetaSVM	Uncertain	0.16	D
PhyloP100		-0.40
PrimateAI	Benign	0.39	T
PROVEAN	Benign	-0.040	N
REVEL	Benign	0.098
Sift	Pathogenic	0.0	D
Vest4		0.10
MutPred		0.28		Gain of helix (P = 0.0164);
MVP		0.75
MPC		0.22
ClinPred		0.23	T
GERP RS		1.7
PromoterAI		-0.037	Neutral
gMVP		0.64
Mutation Taster		=96/4	polymorphism

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

Other links and lift over

dbSNP: rs1225833538; hg19: chr11-44117861;