1-168543937-C-T

Position:

• chr1-168543937-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_003175.4(XCL2):​c.28G>A​(p.Gly10Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 28)
  • Exomes 𝑓: 0.0000014 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: XCL2 NM_003175.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.175

Genes affected

XCL2 (HGNC:10646): (X-C motif chemokine ligand 2) Predicted to enable CCR chemokine receptor binding activity and chemokine activity. Predicted to be involved in several processes, including cellular response to cytokine stimulus; leukocyte chemotaxis; and positive regulation of T cell chemotaxis. Predicted to be located in extracellular region. Predicted to be active in extracellular space. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.08978945).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
XCL2	NM_003175.4	c.28G>A	p.Gly10Ser	missense_variant	1/3	ENST00000367819.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
XCL2	ENST00000367819.3	c.28G>A	p.Gly10Ser	missense_variant	1/3	1	NM_003175.4	P1

Frequencies

GnomAD3 genomes Cov.: 28

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000137 AC: 2 AN: 1459772 Hom.: 0 Cov.: 34 AF XY: 0.00000275 AC XY: 2 AN XY: 726188

Gnomad4 AFR exome AF: 0.0000300

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.00e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 28

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 25, 2022

The c.28G>A (p.G10S) alteration is located in exon 1 (coding exon 1) of the XCL2 gene. This alteration results from a G to A substitution at nucleotide position 28, causing the glycine (G) at amino acid position 10 to be replaced by a serine (S). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.28	T
BayesDel_noAF	Benign	-0.65
CADD	Benign	14
DANN	Benign	0.64
DEOGEN2	Benign	0.0086	T
Eigen	Benign	-0.98
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.012	N
LIST_S2	Benign	0.77	T
M_CAP	Benign	0.0023	T
MetaRNN	Benign	0.090	T
MetaSVM	Benign	-0.92	T
MutationAssessor	Uncertain	2.0	M
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.28	T
PROVEAN	Benign	-0.70	N
REVEL	Benign	0.027
Sift	Benign	0.49	T
Sift4G	Benign	0.60	T
Polyphen		0.21	B
Vest4		0.26
MutPred		0.48		Gain of relative solvent accessibility (P = 0.09);
MVP		0.10
MPC		0.17
ClinPred		0.065	T
GERP RS		0.048
Varity_R		0.072
gMVP		0.28

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

Publications

LitVar

Other links and lift over

dbSNP: rs1654345595; hg19: chr1-168513175;