NM_207122.2:c.-31+496T>G

Variant names:

• chr11-44096348-T-G
• rs11037860
• NM_207122.2:c.-31+496T>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+496T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.717 in 1,531,358 control chromosomes in the GnomAD database, including 395,996 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.71 (37746 hom., cov: 28)
  • Exomes 𝑓: 0.72 (358250 hom.)
• Consequence: EXT2 NM_207122.2 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.96
• Publications: 8 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=-0.88).
• BP6: Variant 11-44096348-T-G is Benign according to our data. Variant chr11-44096348-T-G is described in ClinVar as [Benign]. Clinvar id is 1287445.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.889 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EXT2	NM_207122.2	c.-31+496T>G		intron_variant	Intron 1 of 13	ENST00000533608.7	NP_997005.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
EXT2	ENST00000533608.7	c.-31+496T>G		intron_variant	Intron 1 of 13	1	NM_207122.2	ENSP00000431173.2

Frequencies

GnomAD3 genomes AF: 0.706 AC: 106253 AN: 150574 Hom.: 37705 Cov.: 28

Gnomad AFR AF: 0.615

Gnomad AMI AF: 0.717

Gnomad AMR AF: 0.797

Gnomad ASJ AF: 0.687

Gnomad EAS AF: 0.911

Gnomad SAS AF: 0.736

Gnomad FIN AF: 0.778

Gnomad MID AF: 0.710

Gnomad NFE AF: 0.711

Gnomad OTH AF: 0.712

GnomAD2 exomes AF: 0.751 AC: 101402 AN: 134962 AF XY: 0.748

Gnomad AFR exome AF: 0.608

Gnomad AMR exome AF: 0.849

Gnomad ASJ exome AF: 0.686

Gnomad EAS exome AF: 0.923

Gnomad FIN exome AF: 0.762

Gnomad NFE exome AF: 0.710

Gnomad OTH exome AF: 0.735

GnomAD4 exome AF: 0.719 AC: 992320 AN: 1380666 Hom.: 358250 Cov.: 34 AF XY: 0.719 AC XY: 489668 AN XY: 681166

African (AFR) AF: 0.604 AC: 19000 AN: 31464

American (AMR) AF: 0.844 AC: 30053 AN: 35622

Ashkenazi Jewish (ASJ) AF: 0.685 AC: 17186 AN: 25080

East Asian (EAS) AF: 0.904 AC: 32213 AN: 35630

South Asian (SAS) AF: 0.731 AC: 57857 AN: 79108

European-Finnish (FIN) AF: 0.773 AC: 26158 AN: 33838

Middle Eastern (MID) AF: 0.689 AC: 3677 AN: 5334

European-Non Finnish (NFE) AF: 0.710 AC: 764854 AN: 1076842

Other (OTH) AF: 0.716 AC: 41322 AN: 57748

GnomAD4 genome AF: 0.706 AC: 106352 AN: 150692 Hom.: 37746 Cov.: 28 AF XY: 0.713 AC XY: 52456 AN XY: 73610

African (AFR) AF: 0.616 AC: 25142 AN: 40846

American (AMR) AF: 0.798 AC: 12134 AN: 15214

Ashkenazi Jewish (ASJ) AF: 0.687 AC: 2378 AN: 3460

East Asian (EAS) AF: 0.911 AC: 4638 AN: 5092

South Asian (SAS) AF: 0.737 AC: 3485 AN: 4728

European-Finnish (FIN) AF: 0.778 AC: 8155 AN: 10482

Middle Eastern (MID) AF: 0.712 AC: 208 AN: 292

European-Non Finnish (NFE) AF: 0.711 AC: 48069 AN: 67582

Other (OTH) AF: 0.714 AC: 1493 AN: 2090

Alfa AF: 0.662 Hom.: 4056

Bravo AF: 0.701

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	-0.88
CADD	Benign	2.1
DANN	Benign	0.52
PhyloP100		-2.0
Mutation Taster		=14/86	disease causing (long InDel)

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: rs11037860; hg19: chr11-44117898;