rs16937864

Variant names:

• chr11-44232451-G-A
• rs16937864
• NM_207122.2:c.1761G>A

Your query was ambiguous. Multiple possible variants found:

• chr11-44232451-G-A
• chr11-44232451-G-C

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_000401.3(EXT2):​c.1860G>A​(p.Thr620Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00258 in 1,614,024 control chromosomes in the GnomAD database, including 84 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.013 (39 hom., cov: 32)
  • Exomes 𝑓: 0.0015 (45 hom.)
• Consequence: EXT2 NM_000401.3 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.117
• 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.54).
• BP6: Variant 11-44232451-G-A is Benign according to our data. Variant chr11-44232451-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 304591.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.117 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0133 (2020/152264) while in subpopulation AFR AF = 0.0451 (1873/41540). AF 95% confidence interval is 0.0434. There are 39 homozygotes in GnomAd4. There are 972 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 39 AD,AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000401.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EXT2	NM_207122.2	MANE Select	c.1761G>A	p.Thr587Thr	synonymous	Exon 11 of 14	NP_997005.1
	EXT2	NM_000401.3		c.1860G>A	p.Thr620Thr	synonymous	Exon 11 of 14	NP_000392.3
	EXT2	NM_001178083.3		c.1791G>A	p.Thr597Thr	synonymous	Exon 12 of 15	NP_001171554.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EXT2	ENST00000533608.7	TSL:1 MANE Select	c.1761G>A	p.Thr587Thr	synonymous	Exon 11 of 14	ENSP00000431173.2
	EXT2	ENST00000358681.8	TSL:1	c.1791G>A	p.Thr597Thr	synonymous	Exon 12 of 15	ENSP00000351509.4
	EXT2	ENST00000343631.4	TSL:1	c.1761G>A	p.Thr587Thr	synonymous	Exon 12 of 15	ENSP00000342656.3

Frequencies

GnomAD3 genomes AF: 0.0133 AC: 2016 AN: 152146 Hom.: 39 Cov.: 32

Gnomad AFR AF: 0.0451

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00616

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000942

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.000353

Gnomad OTH AF: 0.0115

GnomAD2 exomes AF: 0.00334 AC: 839 AN: 251214 AF XY: 0.00264

Gnomad AFR exome AF: 0.0434

Gnomad AMR exome AF: 0.00258

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000264

Gnomad OTH exome AF: 0.00163

GnomAD4 exome AF: 0.00147 AC: 2152 AN: 1461760 Hom.: 45 Cov.: 30 AF XY: 0.00123 AC XY: 896 AN XY: 727192

African (AFR) AF: 0.0465 AC: 1556 AN: 33474

American (AMR) AF: 0.00275 AC: 123 AN: 44712

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.000162 AC: 14 AN: 86246

European-Finnish (FIN) AF: 0.0000562 AC: 3 AN: 53400

Middle Eastern (MID) AF: 0.00468 AC: 27 AN: 5766

European-Non Finnish (NFE) AF: 0.000210 AC: 234 AN: 1111950

Other (OTH) AF: 0.00323 AC: 195 AN: 60384

GnomAD4 genome AF: 0.0133 AC: 2020 AN: 152264 Hom.: 39 Cov.: 32 AF XY: 0.0131 AC XY: 972 AN XY: 74454

African (AFR) AF: 0.0451 AC: 1873 AN: 41540

American (AMR) AF: 0.00615 AC: 94 AN: 15292

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.00 AC: 0 AN: 4818

European-Finnish (FIN) AF: 0.0000942 AC: 1 AN: 10618

Middle Eastern (MID) AF: 0.0136 AC: 4 AN: 294

European-Non Finnish (NFE) AF: 0.000353 AC: 24 AN: 68018

Other (OTH) AF: 0.0114 AC: 24 AN: 2112

Alfa AF: 0.00474 Hom.: 27

Bravo AF: 0.0149

Asia WGS AF: 0.00202 AC: 7 AN: 3478

EpiCase AF: 0.000436

EpiControl AF: 0.000356

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	Exostoses, multiple, type 2 (3)
-	-	1	Exostoses, multiple, type 1 (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.54
CADD	Benign	2.4
DANN	Benign	0.70
PhyloP100		-0.12
Mutation Taster		=100/0	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: rs16937864; hg19: chr11-44254001;