chr11-44095894-A-C

Variant names:

• chr11-44095894-A-C
• rs12362775
• NM_207122.2:c.-31+42A>C

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_207122.2(EXT2):​c.-31+42A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000012 in 83,450 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 35)
  • Exomes 𝑓: 0.000012 (0 hom.)
• Consequence: EXT2 NM_207122.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.400
• 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: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EXT2	NM_207122.2	c.-31+42A>C		intron_variant	Intron 1 of 13	ENST00000533608.7	NP_997005.1
EXT2	NM_001178083.3	c.-31+42A>C		intron_variant	Intron 1 of 14		NP_001171554.1
EXT2	NM_001389630.1	c.-70+42A>C		intron_variant	Intron 1 of 14		NP_001376559.1
EXT2	XM_047426529.1	c.-183+42A>C		intron_variant	Intron 1 of 15		XP_047282485.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
EXT2	ENST00000533608.7	c.-31+42A>C		intron_variant	Intron 1 of 13	1	NM_207122.2	ENSP00000431173.2

Frequencies

GnomAD3 genomes Cov.: 35

GnomAD4 exome AF: 0.0000120 AC: 1 AN: 83450 Hom.: 0 Cov.: 0 AF XY: 0.00 AC XY: 0 AN XY: 44352

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 1136

American (AMR) AF: 0.00 AC: 0 AN: 1030

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2318

East Asian (EAS) AF: 0.00 AC: 0 AN: 2526

South Asian (SAS) AF: 0.00 AC: 0 AN: 11432

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 5274

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 358

European-Non Finnish (NFE) AF: 0.0000184 AC: 1 AN: 54312

Other (OTH) AF: 0.00 AC: 0 AN: 5064

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 35

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	11
DANN	Benign	0.38
PhyloP100		0.40
PromoterAI		0.25	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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: rs12362775; hg19: chr11-44117444;