NM_207122.2:c.28C>A

Variant names:

• chr11-44107740-C-A
• rs4755228
• NM_207122.2:c.28C>A

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 0P and 17B. BP4 BP6_Very_Strong BA1

The NM_207122.2(EXT2):​c.28C>A​(p.Arg10Arg) variant causes a synonymous change. The variant allele was found at a frequency of 0.0156 in 1,614,126 control chromosomes in the GnomAD database, including 1,714 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.019 (240 hom., cov: 32)
  • Exomes 𝑓: 0.015 (1474 hom.)
• Consequence: EXT2 NM_207122.2 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 5.73
• Publications: 11 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: Labcorp Genetics (formerly Invitae), G2P, Genomics England PanelApp, ClinGen, Ambry Genetics
• seizures-scoliosis-macrocephaly syndrome

  Inheritance: AR Classification: STRONG, SUPPORTIVE, LIMITED Submitted by: Orphanet, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• hereditary multiple osteochondromas

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -17 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.16).
• BP6: Variant 11-44107740-C-A is Benign according to our data. Variant chr11-44107740-C-A is described in ClinVar as Benign. ClinVar VariationId is 195445.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.268 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_207122.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EXT2	NM_207122.2	MANE Select	c.28C>A	p.Arg10Arg	synonymous	Exon 2 of 14	NP_997005.1	Q93063-1
	EXT2	NM_000401.3		c.127C>A	p.Arg43Arg	synonymous	Exon 2 of 14	NP_000392.3	Q93063-3
	EXT2	NM_001178083.3		c.28C>A	p.Arg10Arg	synonymous	Exon 2 of 15	NP_001171554.1	Q93063-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EXT2	ENST00000533608.7	TSL:1 MANE Select	c.28C>A	p.Arg10Arg	synonymous	Exon 2 of 14	ENSP00000431173.2	Q93063-1
	EXT2	ENST00000358681.8	TSL:1	c.28C>A	p.Arg10Arg	synonymous	Exon 2 of 15	ENSP00000351509.4	Q93063-2
	EXT2	ENST00000343631.4	TSL:1	c.28C>A	p.Arg10Arg	synonymous	Exon 3 of 15	ENSP00000342656.3	Q93063-1

Frequencies

GnomAD3 genomes AF: 0.0192 AC: 2925 AN: 152134 Hom.: 242 Cov.: 32

Gnomad AFR AF: 0.00454

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0315

Gnomad ASJ AF: 0.00577

Gnomad EAS AF: 0.280

Gnomad SAS AF: 0.0599

Gnomad FIN AF: 0.0157

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00447

Gnomad OTH AF: 0.0120

GnomAD2 exomes AF: 0.0354 AC: 8899 AN: 251388 AF XY: 0.0343

Gnomad AFR exome AF: 0.00511

Gnomad AMR exome AF: 0.0355

Gnomad ASJ exome AF: 0.00714

Gnomad EAS exome AF: 0.282

Gnomad FIN exome AF: 0.0150

Gnomad NFE exome AF: 0.00432

Gnomad OTH exome AF: 0.0186

GnomAD4 exome AF: 0.0153 AC: 22314 AN: 1461874 Hom.: 1474 Cov.: 32 AF XY: 0.0161 AC XY: 11688 AN XY: 727242

African (AFR) AF: 0.00349 AC: 117 AN: 33480

American (AMR) AF: 0.0353 AC: 1579 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00627 AC: 164 AN: 26136

East Asian (EAS) AF: 0.251 AC: 9946 AN: 39698

South Asian (SAS) AF: 0.0455 AC: 3923 AN: 86258

European-Finnish (FIN) AF: 0.0148 AC: 790 AN: 53410

Middle Eastern (MID) AF: 0.00555 AC: 32 AN: 5768

European-Non Finnish (NFE) AF: 0.00401 AC: 4461 AN: 1112004

Other (OTH) AF: 0.0216 AC: 1302 AN: 60396

GnomAD4 genome AF: 0.0192 AC: 2925 AN: 152252 Hom.: 240 Cov.: 32 AF XY: 0.0219 AC XY: 1627 AN XY: 74436

African (AFR) AF: 0.00452 AC: 188 AN: 41548

American (AMR) AF: 0.0316 AC: 483 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.00577 AC: 20 AN: 3468

East Asian (EAS) AF: 0.280 AC: 1448 AN: 5170

South Asian (SAS) AF: 0.0603 AC: 291 AN: 4824

European-Finnish (FIN) AF: 0.0157 AC: 166 AN: 10600

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00447 AC: 304 AN: 68024

Other (OTH) AF: 0.0118 AC: 25 AN: 2114

Alfa AF: 0.00848 Hom.: 195

Bravo AF: 0.0208

Asia WGS AF: 0.132 AC: 457 AN: 3478

EpiCase AF: 0.00463

EpiControl AF: 0.00379

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.16
CADD	Benign	13
DANN	Benign	0.67
PhyloP100		5.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=98/2	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: rs4755228; hg19: chr11-44129290; COSMIC: COSV59149768; COSMIC: COSV59149768;