11-44108231-G-C

Variant names:

• chr11-44108231-G-C
• rs148121594
• NM_207122.2:c.519G>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_207122.2(EXT2):​c.519G>C​(p.Ala173Ala) 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:7
• Conservation: PhyloP100: -3.06
• Publications: 3 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 -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 Benign/Likely_benign. ClinVar VariationId is 304577.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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 the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 6 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.519G>C	p.Ala173Ala	synonymous	Exon 2 of 14	NP_997005.1	Q93063-1
	EXT2	NM_000401.3		c.618G>C	p.Ala206Ala	synonymous	Exon 2 of 14	NP_000392.3	Q93063-3
	EXT2	NM_001178083.3		c.519G>C	p.Ala173Ala	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.519G>C	p.Ala173Ala	synonymous	Exon 2 of 14	ENSP00000431173.2	Q93063-1
	EXT2	ENST00000358681.8	TSL:1	c.519G>C	p.Ala173Ala	synonymous	Exon 2 of 15	ENSP00000351509.4	Q93063-2
	EXT2	ENST00000343631.4	TSL:1	c.519G>C	p.Ala173Ala	synonymous	Exon 3 of 15	ENSP00000342656.3	Q93063-1

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

GnomAD2 exomes AF: 0.00624 AC: 1555 AN: 249074 AF XY: 0.00633

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 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

African (AFR) AF: 0.00111 AC: 37 AN: 33476

American (AMR) AF: 0.00179 AC: 80 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00451 AC: 118 AN: 26136

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39694

South Asian (SAS) AF: 0.00205 AC: 177 AN: 86252

European-Finnish (FIN) AF: 0.0123 AC: 639 AN: 52036

Middle Eastern (MID) AF: 0.000520 AC: 3 AN: 5768

European-Non Finnish (NFE) AF: 0.0100 AC: 11122 AN: 1111982

Other (OTH) AF: 0.00601 AC: 363 AN: 60386

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

African (AFR) AF: 0.00195 AC: 81 AN: 41570

American (AMR) AF: 0.00248 AC: 38 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.00634 AC: 22 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.00104 AC: 5 AN: 4822

European-Finnish (FIN) AF: 0.0127 AC: 135 AN: 10606

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

European-Non Finnish (NFE) AF: 0.00973 AC: 662 AN: 68010

Other (OTH) AF: 0.00332 AC: 7 AN: 2108

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

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	2	Exostoses, multiple, type 2 (2)
-	-	1	Exostoses, multiple, type 1 (1)
-	-	1	Exostoses, multiple, type 2;C4225248:Seizures-scoliosis-macrocephaly syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	0.066
DANN	Benign	0.36
PhyloP100		-3.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=89/11	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: rs148121594; hg19: chr11-44129781; COSMIC: COSV59151235;