rs761364688

Variant names:

• chr11-44109209-GAATCAC-G
• rs761364688
• NM_207122.2:c.553_558delAATCAC

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PM4 PP3 PP5

The NM_207122.2(EXT2):​c.553_558delAATCAC​(p.Asn185_His186del) variant causes a conservative inframe deletion change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: EXT2 NM_207122.2 conservative_inframe_deletion
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:1
• Conservation: PhyloP100: 9.20
• 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: Likely_pathogenic. The variant received 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM4: Nonframeshift variant in NON repetitive region in NM_207122.2.
• PP3: No computational evidence supports a deleterious effect, but strongly conserved according to phyloP
• PP5: Variant 11-44109209-GAATCAC-G is Pathogenic according to our data. Variant chr11-44109209-GAATCAC-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 534136.

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.553_558delAATCAC	p.Asn185_His186del	conservative_inframe_deletion	Exon 3 of 14	NP_997005.1
	EXT2	NM_000401.3		c.652_657delAATCAC	p.Asn218_His219del	conservative_inframe_deletion	Exon 3 of 14	NP_000392.3
	EXT2	NM_001178083.3		c.553_558delAATCAC	p.Asn185_His186del	conservative_inframe_deletion	Exon 3 of 15	NP_001171554.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EXT2	ENST00000533608.7	TSL:1 MANE Select	c.553_558delAATCAC	p.Asn185_His186del	conservative_inframe_deletion	Exon 3 of 14	ENSP00000431173.2
	EXT2	ENST00000358681.8	TSL:1	c.553_558delAATCAC	p.Asn185_His186del	conservative_inframe_deletion	Exon 3 of 15	ENSP00000351509.4
	EXT2	ENST00000343631.4	TSL:1	c.553_558delAATCAC	p.Asn185_His186del	conservative_inframe_deletion	Exon 4 of 15	ENSP00000342656.3

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	-	Exostoses, multiple, type 2 (1)
1	-	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		9.2

Splicing

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

Other links and lift over

dbSNP: rs761364688; hg19: chr11-44130759;