rs138899368

chrX-1202479-C-AchrX-1202479-C-T

Variant summary

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

The NM_022148.4(CRLF2):c.406G>T(p.Val136Leu) 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. 13/17 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V136M) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 31)
• Consequence: CRLF2 NM_022148.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0690

Genes affected

CRLF2 (HGNC:14281): (cytokine receptor like factor 2) This gene encodes a member of the type I cytokine receptor family. The encoded protein is a receptor for thymic stromal lymphopoietin (TSLP). Together with the interleukin 7 receptor (IL7R), the encoded protein and TSLP activate STAT3, STAT5, and JAK2 pathways, which control processes such as cell proliferation and development of the hematopoietic system. Rearrangement of this gene with immunoglobulin heavy chain gene (IGH) on chromosome 14, or with P2Y purinoceptor 8 gene (P2RY8) on the same X or Y chromosomes is associated with B-progenitor acute lymphoblastic leukemia (ALL) and Down syndrome ALL. Alternatively spliced transcript variants have been found for this gene. [provided by RefSeq, Sep 2014]

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=0.20258373).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CRLF2	NM_022148.4	c.406G>T	p.Val136Leu	missense_variant	4/8	ENST00000400841.8
CRLF2	NM_001012288.3	c.70G>T	p.Val24Leu	missense_variant	3/7
CRLF2	XM_011546181.3	c.403G>T	p.Val135Leu	missense_variant	4/8
CRLF2	NR_110830.2	n.418G>T		non_coding_transcript_exon_variant	4/8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CRLF2	ENST00000400841.8	c.406G>T	p.Val136Leu	missense_variant	4/8	1	NM_022148.4	P1
CRLF2	ENST00000381567.8	c.70G>T	p.Val24Leu	missense_variant	3/7	1
CRLF2	ENST00000467626.6	c.403G>T	p.Val135Leu	missense_variant, NMD_transcript_variant	4/8	5

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.23	T
BayesDel_noAF	Benign	-0.57
Cadd	Benign	14
Dann	Benign	0.86
DEOGEN2	Benign	0.064	T;T;.
FATHMM_MKL	Benign	0.0030	N
LIST_S2	Benign	0.49	T;.;T
M_CAP	Benign	0.026	D
MetaRNN	Benign	0.20	T;T;T
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	2.0	M;M;.
MutationTaster	Benign	1.0	N;N
PrimateAI	Uncertain	0.70	T
PROVEAN	Benign	-0.66	N;N;.
REVEL	Benign	0.19
Sift	Benign	0.052	T;T;.
Sift4G	Uncertain	0.044	D;D;T
Polyphen		0.97	D;D;.
Vest4		0.27
MutPred		0.66		Gain of phosphorylation at T137 (P = 0.2378);Gain of phosphorylation at T137 (P = 0.2378);.;
MVP		0.53
MPC		0.30
ClinPred		0.47	T
GERP RS		0.32
Varity_R		0.19

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

No publications associated with this variant yet.

Other links and lift over

hg19: chrX-1321349; COSMIC: COSV67494396;