rs199916419

Variant names:

• chr11-44108135-C-G
• rs199916419
• NM_207122.2:c.423C>G

Your query was ambiguous. Multiple possible variants found:

• chr11-44108135-C-G
• chr11-44108135-C-T
• chr11-44108135-C-A

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_207122.2(EXT2):​c.423C>G​(p.Asp141Glu) 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 benign outcome for this variant. 14/24 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as not provided (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D141V) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: EXT2 NM_207122.2 missense
• Clinical Significance: not provided no classification provided O:1
• Conservation: PhyloP100: 0.961
• 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 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 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EXT2	NM_207122.2	MANE Select	c.423C>G	p.Asp141Glu	missense	Exon 2 of 14	NP_997005.1	Q93063-1
	EXT2	NM_000401.3		c.522C>G	p.Asp174Glu	missense	Exon 2 of 14	NP_000392.3	Q93063-3
	EXT2	NM_001178083.3		c.423C>G	p.Asp141Glu	missense	Exon 2 of 15	NP_001171554.1	Q93063-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EXT2	ENST00000533608.7	TSL:1 MANE Select	c.423C>G	p.Asp141Glu	missense	Exon 2 of 14	ENSP00000431173.2	Q93063-1
	EXT2	ENST00000358681.8	TSL:1	c.423C>G	p.Asp141Glu	missense	Exon 2 of 15	ENSP00000351509.4	Q93063-2
	EXT2	ENST00000343631.4	TSL:1	c.423C>G	p.Asp141Glu	missense	Exon 3 of 15	ENSP00000342656.3	Q93063-1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: not provided

Revision: no classification provided

Pathogenic	VUS	Benign	Condition
-	-	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.076
BayesDel_addAF	Benign	-0.029	T
BayesDel_noAF	Benign	-0.28
CADD	Uncertain	24
DANN	Benign	0.93
DEOGEN2	Uncertain	0.54	D
Eigen	Benign	-0.51
Eigen_PC	Benign	-0.26
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Benign	0.83	T
M_CAP	Benign	0.023	T
MetaRNN	Benign	0.17	T
MetaSVM	Uncertain	-0.21	T
MutationAssessor	Benign	-0.27	N
PhyloP100		0.96
PrimateAI	Uncertain	0.62	T
PROVEAN	Benign	0.65	N
REVEL	Benign	0.26
Sift	Benign	0.92	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.079
MutPred		0.57		Gain of sheet (P = 0.1945)
MVP		1.0
MPC		0.20
ClinPred		0.35	T
GERP RS		3.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.076
gMVP		0.44
Mutation Taster		=51/49	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.75		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.75		Position offset: -5

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs199916419; hg19: chr11-44129685;