chr11-44126898-C-T

Variant names:

• chr11-44126898-C-T
• rs141035971
• NM_207122.2:c.1022C>T

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 4P and 5B. PP3_Strong BP6 BS1

The NM_207122.2(EXT2):​c.1022C>T​(p.Pro341Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000763 in 1,614,022 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a pathogenic outcome for this variant. 13/22 in silico tools predict a damaging 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. P341T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00039 (1 hom., cov: 33)
  • Exomes 𝑓: 0.00080 (1 hom.)
• Consequence: EXT2 NM_207122.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:2 O:2
• Conservation: PhyloP100: 7.80
• Publications: 9 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: Likely_benign. The variant received -1 ACMG points.

• PP3: MetaRNN computational evidence supports a deleterious effect, 0.954
• BP6: Variant 11-44126898-C-T is Benign according to our data. Variant chr11-44126898-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 134215.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.000388 (59/152140) while in subpopulation NFE AF = 0.000617 (42/68032). AF 95% confidence interval is 0.000469. There are 1 homozygotes in GnomAd4. There are 27 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

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.1022C>T	p.Pro341Leu	missense	Exon 6 of 14	NP_997005.1	Q93063-1
	EXT2	NM_000401.3		c.1121C>T	p.Pro374Leu	missense	Exon 6 of 14	NP_000392.3	Q93063-3
	EXT2	NM_001178083.3		c.1022C>T	p.Pro341Leu	missense	Exon 6 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.1022C>T	p.Pro341Leu	missense	Exon 6 of 14	ENSP00000431173.2	Q93063-1
	EXT2	ENST00000358681.8	TSL:1	c.1022C>T	p.Pro341Leu	missense	Exon 6 of 15	ENSP00000351509.4	Q93063-2
	EXT2	ENST00000343631.4	TSL:1	c.1022C>T	p.Pro341Leu	missense	Exon 7 of 15	ENSP00000342656.3	Q93063-1

Frequencies

GnomAD3 genomes AF: 0.000388 AC: 59 AN: 152140 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.000314

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000943

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000617

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.000278 AC: 70 AN: 251458 AF XY: 0.000287

Gnomad AFR exome AF: 0.000431

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000139

Gnomad NFE exome AF: 0.000510

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000802 AC: 1173 AN: 1461882 Hom.: 1 Cov.: 32 AF XY: 0.000769 AC XY: 559 AN XY: 727240

African (AFR) AF: 0.000149 AC: 5 AN: 33480

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

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.0000348 AC: 3 AN: 86258

European-Finnish (FIN) AF: 0.000131 AC: 7 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 0.000982 AC: 1092 AN: 1112004

Other (OTH) AF: 0.00108 AC: 65 AN: 60396

GnomAD4 genome AF: 0.000388 AC: 59 AN: 152140 Hom.: 1 Cov.: 33 AF XY: 0.000363 AC XY: 27 AN XY: 74312

African (AFR) AF: 0.000314 AC: 13 AN: 41410

American (AMR) AF: 0.000131 AC: 2 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5196

South Asian (SAS) AF: 0.00 AC: 0 AN: 4822

European-Finnish (FIN) AF: 0.0000943 AC: 1 AN: 10610

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.000617 AC: 42 AN: 68032

Other (OTH) AF: 0.000478 AC: 1 AN: 2090

Alfa AF: 0.000638 Hom.: 0

Bravo AF: 0.000374

TwinsUK AF: 0.00135 AC: 5

ALSPAC AF: 0.00104 AC: 4

ESP6500AA AF: 0.000908 AC: 4

ESP6500EA AF: 0.000930 AC: 8

ExAC AF: 0.000272 AC: 33

EpiCase AF: 0.000545

EpiControl AF: 0.000415

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	2	Exostoses, multiple, type 2 (4)
-	1	-	Exostoses, multiple, type 2;C4225248:Seizures-scoliosis-macrocephaly syndrome (1)
-	1	-	not provided (1)
-	-	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.76
BayesDel_addAF	Pathogenic	0.29	D
BayesDel_noAF	Pathogenic	0.60
CADD	Pathogenic	32
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.98	D
Eigen	Pathogenic	0.97
Eigen_PC	Pathogenic	0.91
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Pathogenic	0.42	D
MetaRNN	Pathogenic	0.95	D
MetaSVM	Pathogenic	0.93	D
MutationAssessor	Pathogenic	3.4	M
PhyloP100		7.8
PrimateAI	Uncertain	0.69	T
PROVEAN	Pathogenic	-9.7	D
REVEL	Pathogenic	0.93
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.99
MVP		1.0
MPC		0.84
ClinPred		0.97	D
GERP RS		5.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.89
gMVP		0.94
Mutation Taster		=15/85	disease causing

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: rs141035971; hg19: chr11-44148448; COSMIC: COSV59151183; COSMIC: COSV59151183;