11-44095822-C-G

Variant names:

• chr11-44095822-C-G
• rs12800404
• NM_207122.2:c.-61C>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.-61C>G 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 0.0504 in 166,824 control chromosomes in the GnomAD database, including 329 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.049 (284 hom., cov: 33)
  • Exomes 𝑓: 0.064 (45 hom.)
• Consequence: EXT2 NM_207122.2 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.43
• 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=-0.57).
• BP6: Variant 11-44095822-C-G is Benign according to our data. Variant chr11-44095822-C-G is described in ClinVar as [Benign]. Clinvar id is 304568.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0767 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EXT2	NM_207122.2	c.-61C>G		5_prime_UTR_premature_start_codon_gain_variant	Exon 1 of 14	ENST00000533608.7	NP_997005.1
EXT2	NM_207122.2	c.-61C>G		5_prime_UTR_variant	Exon 1 of 14	ENST00000533608.7	NP_997005.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
EXT2	ENST00000533608.7	c.-61C>G		5_prime_UTR_premature_start_codon_gain_variant	Exon 1 of 14	1	NM_207122.2	ENSP00000431173.2
EXT2	ENST00000533608.7	c.-61C>G		5_prime_UTR_variant	Exon 1 of 14	1	NM_207122.2	ENSP00000431173.2

Frequencies

GnomAD3 genomes AF: 0.0491 AC: 7471 AN: 152136 Hom.: 284 Cov.: 33

Gnomad AFR AF: 0.0138

Gnomad AMI AF: 0.0230

Gnomad AMR AF: 0.0375

Gnomad ASJ AF: 0.0228

Gnomad EAS AF: 0.000776

Gnomad SAS AF: 0.0186

Gnomad FIN AF: 0.0663

Gnomad MID AF: 0.00318

Gnomad NFE AF: 0.0784

Gnomad OTH AF: 0.0440

GnomAD4 exome AF: 0.0639 AC: 931 AN: 14580 Hom.: 45 Cov.: 0 AF XY: 0.0609 AC XY: 446 AN XY: 7320

African (AFR) AF: 0.0266 AC: 5 AN: 188

American (AMR) AF: 0.0515 AC: 7 AN: 136

Ashkenazi Jewish (ASJ) AF: 0.0213 AC: 8 AN: 376

East Asian (EAS) AF: 0.00 AC: 0 AN: 366

South Asian (SAS) AF: 0.0192 AC: 20 AN: 1040

European-Finnish (FIN) AF: 0.0675 AC: 44 AN: 652

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 60

European-Non Finnish (NFE) AF: 0.0733 AC: 788 AN: 10748

Other (OTH) AF: 0.0582 AC: 59 AN: 1014

GnomAD4 genome AF: 0.0491 AC: 7472 AN: 152244 Hom.: 284 Cov.: 33 AF XY: 0.0474 AC XY: 3526 AN XY: 74428

African (AFR) AF: 0.0138 AC: 575 AN: 41574

American (AMR) AF: 0.0375 AC: 573 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.0228 AC: 79 AN: 3472

East Asian (EAS) AF: 0.000778 AC: 4 AN: 5140

South Asian (SAS) AF: 0.0186 AC: 90 AN: 4832

European-Finnish (FIN) AF: 0.0663 AC: 704 AN: 10616

Middle Eastern (MID) AF: 0.00342 AC: 1 AN: 292

European-Non Finnish (NFE) AF: 0.0784 AC: 5333 AN: 67992

Other (OTH) AF: 0.0435 AC: 92 AN: 2114

Alfa AF: 0.0623 Hom.: 54

Bravo AF: 0.0456

Asia WGS AF: 0.00812 AC: 29 AN: 3464

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Exostoses, multiple, type 2 Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.57
CADD	Benign	19
DANN	Benign	0.89
PhyloP100		1.4
PromoterAI		-0.034	Neutral
Mutation Taster		=297/3	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: rs12800404; hg19: chr11-44117372;