17-50360095-C-G

Variant names:

• chr17-50360095-C-G
• rs6504649
• NM_022167.4:c.2402C>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_022167.4(XYLT2):​c.2402C>G​(p.Thr801Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.367 in 1,613,648 control chromosomes in the GnomAD database, including 112,784 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T801I) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.33 (8965 hom., cov: 33)
  • Exomes 𝑓: 0.37 (103819 hom.)
• Consequence: XYLT2 NM_022167.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6 O:1
• Conservation: PhyloP100: 3.21
• Publications: 41 publications found

Genes affected

XYLT2 (HGNC:15517): (xylosyltransferase 2) The protein encoded by this gene is an isoform of xylosyltransferase, which belongs to a family of glycosyltransferases. This enzyme transfers xylose from UDP-xylose to specific serine residues of the core protein and initiates the biosynthesis of glycosaminoglycan chains in proteoglycans including chondroitin sulfate, heparan sulfate, heparin and dermatan sulfate. The enzyme activity, which is increased in scleroderma patients, is a diagnostic marker for the determination of sclerotic activity in systemic sclerosis. Alternatively spliced transcript variants have been found for this gene. [provided by RefSeq, Dec 2013]

XYLT2 Gene-Disease associations (from GenCC):

• spondylo-ocular syndrome

  Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), G2P

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=2.4977326E-4).
• BP6: Variant 17-50360095-C-G is Benign according to our data. Variant chr17-50360095-C-G is described in ClinVar as Benign. ClinVar VariationId is 2533.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.39 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
XYLT2	NM_022167.4	c.2402C>G	p.Thr801Arg	missense_variant	Exon 11 of 11	ENST00000017003.7	NP_071450.2
XYLT2	XM_005257572.5	c.2306C>G	p.Thr769Arg	missense_variant	Exon 11 of 11		XP_005257629.1
XYLT2	XM_047436522.1	c.1811C>G	p.Thr604Arg	missense_variant	Exon 11 of 11		XP_047292478.1
XYLT2	NR_110010.2	n.2221C>G		non_coding_transcript_exon_variant	Exon 10 of 10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
XYLT2	ENST00000017003.7	c.2402C>G	p.Thr801Arg	missense_variant	Exon 11 of 11	1	NM_022167.4	ENSP00000017003.2

Frequencies

GnomAD3 genomes AF: 0.330 AC: 50095 AN: 152004 Hom.: 8956 Cov.: 33

Gnomad AFR AF: 0.230

Gnomad AMI AF: 0.594

Gnomad AMR AF: 0.293

Gnomad ASJ AF: 0.448

Gnomad EAS AF: 0.0949

Gnomad SAS AF: 0.327

Gnomad FIN AF: 0.411

Gnomad MID AF: 0.386

Gnomad NFE AF: 0.394

Gnomad OTH AF: 0.343

GnomAD2 exomes AF: 0.330 AC: 82635 AN: 250440 AF XY: 0.340

Gnomad AFR exome AF: 0.230

Gnomad AMR exome AF: 0.215

Gnomad ASJ exome AF: 0.454

Gnomad EAS exome AF: 0.0786

Gnomad FIN exome AF: 0.403

Gnomad NFE exome AF: 0.389

Gnomad OTH exome AF: 0.375

GnomAD4 exome AF: 0.371 AC: 541626 AN: 1461526 Hom.: 103819 Cov.: 67 AF XY: 0.372 AC XY: 270374 AN XY: 727052

African (AFR) AF: 0.231 AC: 7730 AN: 33478

American (AMR) AF: 0.224 AC: 10013 AN: 44710

Ashkenazi Jewish (ASJ) AF: 0.447 AC: 11690 AN: 26136

East Asian (EAS) AF: 0.102 AC: 4050 AN: 39698

South Asian (SAS) AF: 0.348 AC: 29976 AN: 86244

European-Finnish (FIN) AF: 0.403 AC: 21477 AN: 53230

Middle Eastern (MID) AF: 0.417 AC: 2405 AN: 5766

European-Non Finnish (NFE) AF: 0.389 AC: 432339 AN: 1111882

Other (OTH) AF: 0.363 AC: 21946 AN: 60382

GnomAD4 genome AF: 0.329 AC: 50123 AN: 152122 Hom.: 8965 Cov.: 33 AF XY: 0.330 AC XY: 24526 AN XY: 74386

African (AFR) AF: 0.230 AC: 9532 AN: 41502

American (AMR) AF: 0.294 AC: 4493 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.448 AC: 1553 AN: 3468

East Asian (EAS) AF: 0.0953 AC: 493 AN: 5174

South Asian (SAS) AF: 0.327 AC: 1578 AN: 4826

European-Finnish (FIN) AF: 0.411 AC: 4339 AN: 10570

Middle Eastern (MID) AF: 0.381 AC: 112 AN: 294

European-Non Finnish (NFE) AF: 0.394 AC: 26762 AN: 67964

Other (OTH) AF: 0.342 AC: 722 AN: 2112

Alfa AF: 0.347 Hom.: 3008

Bravo AF: 0.314

TwinsUK AF: 0.392 AC: 1453

ALSPAC AF: 0.396 AC: 1526

ESP6500AA AF: 0.241 AC: 1064

ESP6500EA AF: 0.398 AC: 3418

ExAC AF: 0.331 AC: 40211

Asia WGS AF: 0.196 AC: 679 AN: 3478

EpiCase AF: 0.398

EpiControl AF: 0.392

ClinVar

Significance: Benign

Submissions summary: Benign:6 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Nov 25, 2020

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 16571645) -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Spondylo-ocular syndrome Benign:2

Dec 05, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 28, 2019

Mendelics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Osteogenesis imperfecta Benign:1

Jul 16, 2022

Genome Diagnostics Laboratory, The Hospital for Sick Children

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

PSEUDOXANTHOMA ELASTICUM, MODIFIER OF SEVERITY OF Other:1

Sep 01, 2006

OMIM

Significance: risk factor

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.093
BayesDel_addAF	Benign	-0.67	T
BayesDel_noAF	Benign	-0.60
CADD	Benign	13
DANN	Benign	0.90
DEOGEN2	Benign	0.079	T
Eigen	Benign	-0.81
Eigen_PC	Benign	-0.82
FATHMM_MKL	Benign	0.46	N
LIST_S2	Benign	0.81	T
MetaRNN	Benign	0.00025	T
MetaSVM	Benign	-0.91	T
MutationAssessor	Benign	0.34	N
PhyloP100		3.2
PrimateAI	Benign	0.35	T
PROVEAN	Benign	-1.6	N
REVEL	Benign	0.11
Sift	Benign	0.050	D
Sift4G	Uncertain	0.046	D
Polyphen		0.025	B
Vest4		0.056
MPC		0.50
ClinPred		0.011	T
GERP RS		1.9
Varity_R		0.063
gMVP		0.79
Mutation Taster		=92/8	polymorphism (auto)

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: rs6504649; hg19: chr17-48437456; COSMIC: COSV50017604; COSMIC: COSV50017604;