NM_207122.2:c.-26G>A

Variant names:

• chr11-44107687-G-A
• rs369437823
• NM_207122.2:c.-26G>A

Variant summary

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

The NM_207122.2(EXT2):​c.-26G>A variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000206 in 1,456,004 control chromosomes in the GnomAD database, with no homozygous occurrence. 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)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: EXT2 NM_207122.2 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.87
• Publications: 2 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=0.16588068).

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.-26G>A		5_prime_UTR_premature_start_codon_gain	Exon 2 of 14	NP_997005.1	Q93063-1
	EXT2	NM_207122.2	MANE Select	c.-26G>A		5_prime_UTR	Exon 2 of 14	NP_997005.1	Q93063-1
	EXT2	NM_001178083.3		c.-26G>A		5_prime_UTR_premature_start_codon_gain	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.-26G>A		5_prime_UTR_premature_start_codon_gain	Exon 2 of 14	ENSP00000431173.2	Q93063-1
	EXT2	ENST00000358681.8	TSL:1	c.-26G>A		5_prime_UTR_premature_start_codon_gain	Exon 2 of 15	ENSP00000351509.4	Q93063-2
	EXT2	ENST00000343631.4	TSL:1	c.-26G>A		5_prime_UTR_premature_start_codon_gain	Exon 3 of 15	ENSP00000342656.3	Q93063-1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000399 AC: 1 AN: 250474 AF XY: 0.00000739

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000883

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000206 AC: 3 AN: 1456004 Hom.: 0 Cov.: 32 AF XY: 0.00000277 AC XY: 2 AN XY: 722942

African (AFR) AF: 0.00 AC: 0 AN: 33366

American (AMR) AF: 0.00 AC: 0 AN: 44618

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26054

East Asian (EAS) AF: 0.00 AC: 0 AN: 39540

South Asian (SAS) AF: 0.00 AC: 0 AN: 86064

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53304

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5750

European-Non Finnish (NFE) AF: 0.00000271 AC: 3 AN: 1107170

Other (OTH) AF: 0.00 AC: 0 AN: 60138

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000824 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.077
BayesDel_addAF	Uncertain	0.045	T
BayesDel_noAF	Benign	-0.17
CADD	Benign	18
DANN	Uncertain	1.0
Eigen	Benign	-0.18
Eigen_PC	Benign	0.011
FATHMM_MKL	Benign	0.46	N
LIST_S2	Benign	0.49	T
M_CAP	Benign	0.044	D
MetaRNN	Benign	0.17	T
MetaSVM	Uncertain	-0.090	T
PhyloP100		1.9
PrimateAI	Benign	0.34	T
PROVEAN	Benign	-0.020	N
REVEL	Benign	0.26
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Vest4		0.31
MutPred		0.39		Gain of phosphorylation at C25 (P = 0.0191)
MVP		0.85
MPC		0.75
ClinPred		0.37	T
GERP RS		5.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
gMVP		0.40
Mutation Taster		=92/8	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs369437823; hg19: chr11-44129237;