rs1057519743

chrX-1196852-A-C

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PS1 PM2 PP5

The NM_022148.4(CRLF2):c.695T>G(p.Phe232Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (no stars). Another nucleotide change resulting in same amino acid change has been previously reported as Pathogenicin ClinVar.

• Frequency: Genomes: not found (cov: 31)
• Consequence: CRLF2 NM_022148.4 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 0.523

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 Likely_pathogenic. Variant got 7 ACMG points.

• PS1: Transcript NM_022148.4 (CRLF2) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in ClinVar as 376003
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant X-1196852-A-C is Pathogenic according to our data. Variant chrX-1196852-A-C is described in ClinVar as [Pathogenic]. Clinvar id is 376003.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CRLF2	NM_022148.4	c.695T>G	p.Phe232Cys	missense_variant	6/8	ENST00000400841.8
CRLF2	NM_001012288.3	c.359T>G	p.Phe120Cys	missense_variant	5/7
CRLF2	XM_011546181.3	c.692T>G	p.Phe231Cys	missense_variant	6/8
CRLF2	NR_110830.2	n.889T>G		non_coding_transcript_exon_variant	6/8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CRLF2	ENST00000400841.8	c.695T>G	p.Phe232Cys	missense_variant	6/8	1	NM_022148.4	P1
CRLF2	ENST00000381567.8	c.359T>G	p.Phe120Cys	missense_variant	5/7	1
CRLF2	ENST00000467626.6	c.*175T>G		3_prime_UTR_variant, NMD_transcript_variant	6/8	5

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 31

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Lymphoblastic leukemia, acute, with lymphomatous features Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

Database of Curated Mutations (DoCM)

Oct 02, 2014

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.20	D
BayesDel_noAF	Uncertain	0.050
Cadd	Benign	17
DEOGEN2	Benign	0.16	T;T;.
FATHMM_MKL	Benign	0.017	N
LIST_S2	Benign	0.41	T;.;T
M_CAP	Uncertain	0.15	D
MetaRNN	Uncertain	0.58	D;D;D
MetaSVM	Uncertain	0.57	D
MutationAssessor	Benign	1.8	L;L;.
MutationTaster	Benign	1.0	N
PrimateAI	Uncertain	0.62	T
Sift4G	Uncertain	0.0060	D;D;D
Polyphen		1.0	D;D;.
Vest4		0.54
MutPred		0.46		Loss of stability (P = 0.0164);Loss of stability (P = 0.0164);.;
MVP		0.80
MPC		0.43
ClinPred		0.66	D
GERP RS		1.6
Varity_R		0.13

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1057519743; hg19: chrX-1314966; COSMIC: COSV67493408;