chr11-44107976-C-T

Variant names:

• chr11-44107976-C-T
• rs35455466
• NM_207122.2:c.264C>T

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BS1 BS2

The NM_207122.2(EXT2):​c.264C>T​(p.His88His) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0024 in 1,614,210 control chromosomes in the GnomAD database, including 77 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.012 (42 hom., cov: 32)
  • Exomes 𝑓: 0.0014 (35 hom.)
• Consequence: EXT2 NM_207122.2 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 1.36
• 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 -18 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.36).
• BP6: Variant 11-44107976-C-T is Benign according to our data. Variant chr11-44107976-C-T is described in ClinVar as Benign. ClinVar VariationId is 304576.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0125 (1901/152346) while in subpopulation AFR AF = 0.0432 (1794/41570). AF 95% confidence interval is 0.0415. There are 42 homozygotes in GnomAd4. There are 921 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 42 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.264C>T	p.His88His	synonymous	Exon 2 of 14	NP_997005.1	Q93063-1
	EXT2	NM_000401.3		c.363C>T	p.His121His	synonymous	Exon 2 of 14	NP_000392.3	Q93063-3
	EXT2	NM_001178083.3		c.264C>T	p.His88His	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.264C>T	p.His88His	synonymous	Exon 2 of 14	ENSP00000431173.2	Q93063-1
	EXT2	ENST00000358681.8	TSL:1	c.264C>T	p.His88His	synonymous	Exon 2 of 15	ENSP00000351509.4	Q93063-2
	EXT2	ENST00000343631.4	TSL:1	c.264C>T	p.His88His	synonymous	Exon 3 of 15	ENSP00000342656.3	Q93063-1

Frequencies

GnomAD3 genomes AF: 0.0124 AC: 1895 AN: 152228 Hom.: 42 Cov.: 32

Gnomad AFR AF: 0.0431

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00438

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000620

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000235

Gnomad OTH AF: 0.0100

GnomAD2 exomes AF: 0.00326 AC: 818 AN: 251200 AF XY: 0.00243

Gnomad AFR exome AF: 0.0439

Gnomad AMR exome AF: 0.00203

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000176

Gnomad OTH exome AF: 0.00179

GnomAD4 exome AF: 0.00135 AC: 1979 AN: 1461864 Hom.: 35 Cov.: 32 AF XY: 0.00123 AC XY: 893 AN XY: 727232

African (AFR) AF: 0.0460 AC: 1541 AN: 33480

American (AMR) AF: 0.00268 AC: 120 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39696

South Asian (SAS) AF: 0.0000927 AC: 8 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53416

Middle Eastern (MID) AF: 0.00347 AC: 20 AN: 5768

European-Non Finnish (NFE) AF: 0.0000845 AC: 94 AN: 1112002

Other (OTH) AF: 0.00325 AC: 196 AN: 60394

GnomAD4 genome AF: 0.0125 AC: 1901 AN: 152346 Hom.: 42 Cov.: 32 AF XY: 0.0124 AC XY: 921 AN XY: 74498

African (AFR) AF: 0.0432 AC: 1794 AN: 41570

American (AMR) AF: 0.00438 AC: 67 AN: 15306

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.000621 AC: 3 AN: 4832

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: 0.000235 AC: 16 AN: 68036

Other (OTH) AF: 0.00992 AC: 21 AN: 2116

Alfa AF: 0.00624 Hom.: 8

Bravo AF: 0.0141

Asia WGS AF: 0.00462 AC: 16 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.000237

ClinVar

ClinVar submissions

Significance: 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)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.36
CADD	Benign	8.0
DANN	Benign	0.64
PhyloP100		1.4
Mutation Taster		=94/6	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: rs35455466; hg19: chr11-44129526;