11-44095894-A-G

Variant names:

• chr11-44095894-A-G
• rs12362775
• NM_207122.2:c.-31+42A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_207122.2(EXT2):​c.-31+42A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.725 in 235,268 control chromosomes in the GnomAD database, including 62,257 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.72 (39621 hom., cov: 35)
  • Exomes 𝑓: 0.74 (22636 hom.)
• Consequence: EXT2 NM_207122.2 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.400
• 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: 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BP6: Variant 11-44095894-A-G is Benign according to our data. Variant chr11-44095894-A-G is described in ClinVar as [Benign]. Clinvar id is 1236902.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.89 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EXT2	NM_207122.2	c.-31+42A>G		intron_variant	Intron 1 of 13	ENST00000533608.7	NP_997005.1
EXT2	NM_001178083.3	c.-31+42A>G		intron_variant	Intron 1 of 14		NP_001171554.1
EXT2	NM_001389630.1	c.-70+42A>G		intron_variant	Intron 1 of 14		NP_001376559.1
EXT2	XM_047426529.1	c.-183+42A>G		intron_variant	Intron 1 of 15		XP_047282485.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
EXT2	ENST00000533608.7	c.-31+42A>G		intron_variant	Intron 1 of 13	1	NM_207122.2	ENSP00000431173.2

Frequencies

GnomAD3 genomes AF: 0.720 AC: 109332 AN: 151922 Hom.: 39572 Cov.: 35

Gnomad AFR AF: 0.668

Gnomad AMI AF: 0.714

Gnomad AMR AF: 0.804

Gnomad ASJ AF: 0.687

Gnomad EAS AF: 0.911

Gnomad SAS AF: 0.732

Gnomad FIN AF: 0.775

Gnomad MID AF: 0.717

Gnomad NFE AF: 0.710

Gnomad OTH AF: 0.723

GnomAD4 exome AF: 0.735 AC: 61183 AN: 83238 Hom.: 22636 Cov.: 0 AF XY: 0.735 AC XY: 32522 AN XY: 44224

African (AFR) AF: 0.676 AC: 763 AN: 1128

American (AMR) AF: 0.842 AC: 866 AN: 1028

Ashkenazi Jewish (ASJ) AF: 0.691 AC: 1596 AN: 2310

East Asian (EAS) AF: 0.886 AC: 2237 AN: 2524

South Asian (SAS) AF: 0.753 AC: 8598 AN: 11412

European-Finnish (FIN) AF: 0.780 AC: 4102 AN: 5258

Middle Eastern (MID) AF: 0.688 AC: 245 AN: 356

European-Non Finnish (NFE) AF: 0.722 AC: 39137 AN: 54172

Other (OTH) AF: 0.721 AC: 3639 AN: 5050

GnomAD4 genome AF: 0.720 AC: 109437 AN: 152030 Hom.: 39621 Cov.: 35 AF XY: 0.726 AC XY: 53974 AN XY: 74320

African (AFR) AF: 0.668 AC: 27725 AN: 41482

American (AMR) AF: 0.804 AC: 12295 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.687 AC: 2384 AN: 3472

East Asian (EAS) AF: 0.911 AC: 4694 AN: 5150

South Asian (SAS) AF: 0.733 AC: 3544 AN: 4832

European-Finnish (FIN) AF: 0.775 AC: 8184 AN: 10556

Middle Eastern (MID) AF: 0.719 AC: 210 AN: 292

European-Non Finnish (NFE) AF: 0.710 AC: 48217 AN: 67934

Other (OTH) AF: 0.726 AC: 1534 AN: 2114

Alfa AF: 0.715 Hom.: 4830

Bravo AF: 0.720

Asia WGS AF: 0.797 AC: 2751 AN: 3456

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jul 27, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	11
DANN	Benign	0.43
PhyloP100		0.40
PromoterAI		0.047	Neutral
Mutation Taster		=100/0	polymorphism (auto)

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: rs12362775; hg19: chr11-44117444;