NM_207122.2:c.1123A>G

Variant names:

• chr11-44130088-A-G
• rs369029338
• NM_207122.2:c.1123A>G

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_207122.2(EXT2):​c.1123A>G​(p.Ser375Gly) variant causes a missense change. The variant allele was found at a frequency of 0.000385 in 1,614,242 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S375N) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00029 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00040 (3 hom.)
• Consequence: EXT2 NM_207122.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:2 O:1
• Conservation: PhyloP100: 5.14
• Publications: 2 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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.010539144).
• BP6: Variant 11-44130088-A-G is Benign according to our data. Variant chr11-44130088-A-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 134216.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.000289 (44/152360) while in subpopulation SAS AF = 0.00827 (40/4834). AF 95% confidence interval is 0.00625. There are 0 homozygotes in GnomAd4. There are 31 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 3 AD,AR gene

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.1123A>G	p.Ser375Gly	missense	Exon 7 of 14	NP_997005.1	Q93063-1
	EXT2	NM_000401.3		c.1222A>G	p.Ser408Gly	missense	Exon 7 of 14	NP_000392.3	Q93063-3
	EXT2	NM_001178083.3		c.1123A>G	p.Ser375Gly	missense	Exon 7 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.1123A>G	p.Ser375Gly	missense	Exon 7 of 14	ENSP00000431173.2	Q93063-1
	EXT2	ENST00000358681.8	TSL:1	c.1123A>G	p.Ser375Gly	missense	Exon 7 of 15	ENSP00000351509.4	Q93063-2
	EXT2	ENST00000343631.4	TSL:1	c.1123A>G	p.Ser375Gly	missense	Exon 8 of 15	ENSP00000342656.3	Q93063-1

Frequencies

GnomAD3 genomes AF: 0.000289 AC: 44 AN: 152242 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00827

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.000955

GnomAD2 exomes AF: 0.000859 AC: 216 AN: 251456 AF XY: 0.00109

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.0000992

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000176

Gnomad OTH exome AF: 0.000489

GnomAD4 exome AF: 0.000395 AC: 578 AN: 1461882 Hom.: 3 Cov.: 31 AF XY: 0.000561 AC XY: 408 AN XY: 727244

African (AFR) AF: 0.0000299 AC: 1 AN: 33480

American (AMR) AF: 0.0000224 AC: 1 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0000383 AC: 1 AN: 26136

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39700

South Asian (SAS) AF: 0.00621 AC: 536 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.0000117 AC: 13 AN: 1112004

Other (OTH) AF: 0.000397 AC: 24 AN: 60392

GnomAD4 genome AF: 0.000289 AC: 44 AN: 152360 Hom.: 0 Cov.: 32 AF XY: 0.000416 AC XY: 31 AN XY: 74502

African (AFR) AF: 0.00 AC: 0 AN: 41582

American (AMR) AF: 0.00 AC: 0 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

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

South Asian (SAS) AF: 0.00827 AC: 40 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

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

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 68040

Other (OTH) AF: 0.000945 AC: 2 AN: 2116

Alfa AF: 0.00000950 Hom.: 0

Bravo AF: 0.0000642

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.00105 AC: 127

Asia WGS AF: 0.00404 AC: 14 AN: 3478

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.057
BayesDel_addAF	Benign	-0.23	T
BayesDel_noAF	Benign	-0.10
CADD	Benign	18
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.81	D
Eigen	Benign	-0.025
Eigen_PC	Benign	0.17
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.76	T
MetaRNN	Benign	0.011	T
MetaSVM	Uncertain	0.66	D
MutationAssessor	Benign	1.4	L
PhyloP100		5.1
PrimateAI	Benign	0.32	T
PROVEAN	Benign	-2.2	N
REVEL	Uncertain	0.39
Sift	Benign	0.089	T
Sift4G	Benign	0.34	T
Polyphen		0.0010	B
Vest4		0.13
MVP		0.99
MPC		0.20
ClinPred		0.045	T
GERP RS		5.7
Varity_R		0.14
gMVP		0.42
Mutation Taster		=98/2	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs369029338; hg19: chr11-44151638;