11-44096298-C-G

Variant names:

• chr11-44096298-C-G
• rs1319047047
• ENST00000343631.4:c.-54C>G

Variant summary

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

The NM_000401.3(EXT2):​c.46C>G​(p.Arg16Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000217 in 1,383,686 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/20 in silico tools predict a benign 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. R16R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000022 (0 hom.)
• Consequence: EXT2 NM_000401.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.672
• 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: 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

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=0.078517884).

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.-31+446C>G		intron	N/A	NP_997005.1	Q93063-1
	EXT2	NM_000401.3		c.46C>G	p.Arg16Gly	missense	Exon 1 of 14	NP_000392.3	Q93063-3
	EXT2	NM_001389628.1		c.-54C>G		5_prime_UTR	Exon 1 of 14	NP_001376557.1	Q93063-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EXT2	ENST00000343631.4	TSL:1	c.-54C>G		5_prime_UTR	Exon 2 of 15	ENSP00000342656.3	Q93063-1
	EXT2	ENST00000533608.7	TSL:1 MANE Select	c.-31+446C>G		intron	N/A	ENSP00000431173.2	Q93063-1
	EXT2	ENST00000358681.8	TSL:1	c.-31+446C>G		intron	N/A	ENSP00000351509.4	Q93063-2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000217 AC: 3 AN: 1383686 Hom.: 0 Cov.: 32 AF XY: 0.00000293 AC XY: 2 AN XY: 682810

African (AFR) AF: 0.00 AC: 0 AN: 31586

American (AMR) AF: 0.00 AC: 0 AN: 35700

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25170

East Asian (EAS) AF: 0.00 AC: 0 AN: 35724

South Asian (SAS) AF: 0.00 AC: 0 AN: 79230

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 33904

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5684

European-Non Finnish (NFE) AF: 0.00000278 AC: 3 AN: 1078796

Other (OTH) AF: 0.00 AC: 0 AN: 57892

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.073
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.42
CADD	Benign	6.0
DANN	Benign	0.73
Eigen	Benign	-0.79
Eigen_PC	Benign	-0.99
FATHMM_MKL	Benign	0.015	N
LIST_S2	Benign	0.45	T
M_CAP	Benign	0.0084	T
MetaRNN	Benign	0.079	T
MetaSVM	Uncertain	-0.21	T
PhyloP100		-0.67
PrimateAI	Benign	0.31	T
PROVEAN	Benign	0.010	N
REVEL	Benign	0.12
Sift	Benign	0.44	T
Sift4G	Pathogenic	0.0	D
Vest4		0.11
MutPred		0.20		Gain of methylation at K19 (P = 0.0568)
MVP		0.63
MPC		0.28
ClinPred		0.044	T
GERP RS		-0.93
PromoterAI		-0.017	Neutral
gMVP		0.77
Mutation Taster		=95/5	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: rs1319047047; hg19: chr11-44117848;