1-168541046-A-G

Position:

• chr1-168541046-A-G

Variant summary

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

The NM_003175.4(XCL2):​c.251T>C​(p.Met84Thr) variant causes a missense change. The variant allele was found at a frequency of 0.00000137 in 1,461,404 control chromosomes in the GnomAD database, with no homozygous occurrence. 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: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: XCL2 NM_003175.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.62

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=0.12783489).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
XCL2	NM_003175.4	c.251T>C	p.Met84Thr	missense_variant	3/3	ENST00000367819.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
XCL2	ENST00000367819.3	c.251T>C	p.Met84Thr	missense_variant	3/3	1	NM_003175.4	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461404 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 726996

Gnomad4 AFR exome AF: 0.00

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: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

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

Jan 30, 2024

The c.251T>C (p.M84T) alteration is located in exon 3 (coding exon 3) of the XCL2 gene. This alteration results from a T to C substitution at nucleotide position 251, causing the methionine (M) at amino acid position 84 to be replaced by a threonine (T). 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	0.32
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Benign	-0.47
CADD	Benign	19
DANN	Benign	0.73
DEOGEN2	Benign	0.074	T
Eigen	Benign	-0.67
Eigen_PC	Benign	-0.76
FATHMM_MKL	Benign	0.095	N
LIST_S2	Benign	0.30	T
M_CAP	Benign	0.0078	T
MetaRNN	Benign	0.13	T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	2.0	M
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.36	T
PROVEAN	Uncertain	-2.6	D
REVEL	Benign	0.17
Sift	Uncertain	0.010	D
Sift4G	Uncertain	0.019	D
Polyphen		0.22	B
Vest4		0.32
MVP		0.13
MPC		0.29
ClinPred		0.23	T
GERP RS		2.4
Varity_R		0.26
gMVP		0.41

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: rs146141295; hg19: chr1-168510284;