rs372901342

Variant names:

• chr11-44232500-AG-A
• rs372901342
• NM_207122.2:c.1806+9delG

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP6_Moderate BS1

The ENST00000533608.7(EXT2):​c.1806+5delG variant causes a splice region, intron change. The variant allele was found at a frequency of 0.0000514 in 1,613,850 control chromosomes in the GnomAD database, including 1 homozygotes. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.00019 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000037 (1 hom.)
• Consequence: EXT2 ENST00000533608.7 splice_region, intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 4.42
• 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_benign. The variant received -6 ACMG points.

• BP6: Variant 11-44232500-AG-A is Benign according to our data. Variant chr11-44232500-AG-A is described in ClinVar as Benign. ClinVar VariationId is 465698.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00019 (29/152278) while in subpopulation AFR AF = 0.000626 (26/41560). AF 95% confidence interval is 0.000438. There are 0 homozygotes in GnomAd4. There are 15 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000533608.7. 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.1806+9delG		intron	N/A	NP_997005.1
	EXT2	NM_000401.3		c.1905+9delG		intron	N/A	NP_000392.3
	EXT2	NM_001178083.3		c.1836+9delG		intron	N/A	NP_001171554.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EXT2	ENST00000533608.7	TSL:1 MANE Select	c.1806+5delG		splice_region intron	N/A	ENSP00000431173.2
	EXT2	ENST00000358681.8	TSL:1	c.1836+5delG		splice_region intron	N/A	ENSP00000351509.4
	EXT2	ENST00000343631.4	TSL:1	c.1806+5delG		splice_region intron	N/A	ENSP00000342656.3

Frequencies

GnomAD3 genomes AF: 0.000184 AC: 28 AN: 152160 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000603

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000199 AC: 5 AN: 250918 AF XY: 0.00000737

Gnomad AFR exome AF: 0.000246

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: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000369 AC: 54 AN: 1461572 Hom.: 1 Cov.: 30 AF XY: 0.0000481 AC XY: 35 AN XY: 727080

African (AFR) AF: 0.00108 AC: 36 AN: 33464

American (AMR) AF: 0.0000224 AC: 1 AN: 44706

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26130

East Asian (EAS) AF: 0.00 AC: 0 AN: 39688

South Asian (SAS) AF: 0.0000464 AC: 4 AN: 86228

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53382

Middle Eastern (MID) AF: 0.000867 AC: 5 AN: 5766

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111836

Other (OTH) AF: 0.000116 AC: 7 AN: 60372

GnomAD4 genome AF: 0.000190 AC: 29 AN: 152278 Hom.: 0 Cov.: 32 AF XY: 0.000201 AC XY: 15 AN XY: 74454

African (AFR) AF: 0.000626 AC: 26 AN: 41560

American (AMR) AF: 0.00 AC: 0 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.000208 AC: 1 AN: 4818

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 68004

Other (OTH) AF: 0.00 AC: 0 AN: 2112

Alfa AF: 0.000214 Hom.: 0

Bravo AF: 0.000253

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	Exostoses, multiple, type 2 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		4.4
Mutation Taster		=99/1	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: rs372901342; hg19: chr11-44254050;