11-44108231-G-C

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_207122.2(EXT2):c.519G>C(p.Ala173=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00836 in 1,612,728 control chromosomes in the GnomAD database, including 69 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. A173A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0062 (6 hom., cov: 32)
  • Exomes 𝑓: 0.0086 (63 hom.)
• Consequence: EXT2 NM_207122.2 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -3.06

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]

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BP6: Variant 11-44108231-G-C is Benign according to our data. Variant chr11-44108231-G-C is described in ClinVar as [Likely_benign]. Clinvar id is 304577.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-44108231-G-C is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-3.07 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00624 (950/152276) while in subpopulation NFE AF= 0.00973 (662/68010). AF 95% confidence interval is 0.00912. There are 6 homozygotes in gnomad4. There are 457 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd at 949 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
EXT2	NM_207122.2	c.519G>C	p.Ala173=	synonymous_variant	2/14	ENST00000533608.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
EXT2	ENST00000533608.7	c.519G>C	p.Ala173=	synonymous_variant	2/14	1	NM_207122.2	P1

Frequencies

GnomAD3 genomes AF: 0.00624 AC: 949 AN: 152158 Hom.: 6 Cov.: 32

Gnomad AFR AF: 0.00195

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00249

Gnomad ASJ AF: 0.00634

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000829

Gnomad FIN AF: 0.0127

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00973

Gnomad OTH AF: 0.00336

GnomAD3 exomes AF: 0.00624 AC: 1555 AN: 249074 Hom.: 9 AF XY: 0.00633 AC XY: 853 AN XY: 134846

Gnomad AFR exome AF: 0.00185

Gnomad AMR exome AF: 0.00200

Gnomad ASJ exome AF: 0.00397

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00196

Gnomad FIN exome AF: 0.0146

Gnomad NFE exome AF: 0.00918

Gnomad OTH exome AF: 0.00392

GnomAD4 exome AF: 0.00859 AC: 12540 AN: 1460452 Hom.: 63 Cov.: 32 AF XY: 0.00844 AC XY: 6133 AN XY: 726570

Gnomad4 AFR exome AF: 0.00111

Gnomad4 AMR exome AF: 0.00179

Gnomad4 ASJ exome AF: 0.00451

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00205

Gnomad4 FIN exome AF: 0.0123

Gnomad4 NFE exome AF: 0.0100

Gnomad4 OTH exome AF: 0.00601

GnomAD4 genome AF: 0.00624 AC: 950 AN: 152276 Hom.: 6 Cov.: 32 AF XY: 0.00614 AC XY: 457 AN XY: 74452

Gnomad4 AFR AF: 0.00195

Gnomad4 AMR AF: 0.00248

Gnomad4 ASJ AF: 0.00634

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00104

Gnomad4 FIN AF: 0.0127

Gnomad4 NFE AF: 0.00973

Gnomad4 OTH AF: 0.00332

Alfa AF: 0.00520 Hom.: 1

Bravo AF: 0.00502

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.00769

EpiControl AF: 0.00599

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Exostoses, multiple, type 2 Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	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. -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 26, 2024	- -

Exostoses, multiple, type 2;C4225248:Seizures-scoliosis-macrocephaly syndrome Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Sep 14, 2021

- -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Oct 01, 2023

EXT2: BP4, BP7, BS2 -

Exostoses, multiple, type 1 Benign:1

Benign, criteria provided, single submitter

clinical testing

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Jul 07, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
Cadd	Benign	0.066
Dann	Benign	0.36
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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

Publications

LitVar

Other links and lift over

dbSNP: rs148121594; hg19: chr11-44129781; COSMIC: COSV59151235; COSMIC: COSV59151235;