X-1196817-C-G

Variant names:

• chrX-1196817-C-G
• rs151218732
• NM_022148.4:c.730G>C

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 1P and 6B. PP2 BP4_Moderate BS2

The NM_022148.4(CRLF2):​c.730G>C​(p.Val244Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000434 in 1,612,648 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 4 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 11/14 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. V244M) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., 1 hem., cov: 31)
  • Exomes 𝑓: 0.0000041 (0 hom. 3 hem.)
• Consequence: CRLF2 NM_022148.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.856
• Publications: 0 publications found

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

Our verdict: Likely_benign. The variant received -5 ACMG points.

• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 1 curated pathogenic missense variants (we use a threshold of 10). The gene has 0 curated benign missense variants. Gene score misZ: -0.85264 (below the threshold of 3.09). Trascript score misZ: NaN (below the threshold of 3.09).
• BP4: Computational evidence support a benign effect (MetaRNN=0.17448077).
• BS2: High Hemizygotes in GnomAdExome4 at 3 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CRLF2	NM_022148.4	c.730G>C	p.Val244Leu	missense_variant	Exon 6 of 8	ENST00000400841.8	NP_071431.2
CRLF2	NM_001012288.3	c.394G>C	p.Val132Leu	missense_variant	Exon 5 of 7		NP_001012288.2
CRLF2	XM_011546181.3	c.727G>C	p.Val243Leu	missense_variant	Exon 6 of 8		XP_011544483.1
CRLF2	NR_110830.2	n.924G>C		non_coding_transcript_exon_variant	Exon 6 of 8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CRLF2	ENST00000400841.8	c.730G>C	p.Val244Leu	missense_variant	Exon 6 of 8	1	NM_022148.4	ENSP00000383641.3
CRLF2	ENST00000381567.8	c.394G>C	p.Val132Leu	missense_variant	Exon 5 of 7	1		ENSP00000370979.4
CRLF2	ENST00000467626.6	n.*210G>C		non_coding_transcript_exon_variant	Exon 6 of 8	5		ENSP00000485269.1
CRLF2	ENST00000467626.6	n.*210G>C		3_prime_UTR_variant	Exon 6 of 8	5		ENSP00000485269.1

Frequencies

GnomAD3 genomes AF: 0.00000659 AC: 1 AN: 151648 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.0000242

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000411 AC: 6 AN: 1461000 Hom.: 0 Cov.: 32 AF XY: 0.00000413 AC XY: 3 AN XY: 726776

African (AFR) AF: 0.0000299 AC: 1 AN: 33452

American (AMR) AF: 0.00 AC: 0 AN: 44676

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26124

East Asian (EAS) AF: 0.00 AC: 0 AN: 39670

South Asian (SAS) AF: 0.00 AC: 0 AN: 86198

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53384

Middle Eastern (MID) AF: 0.000174 AC: 1 AN: 5754

European-Non Finnish (NFE) AF: 0.00000360 AC: 4 AN: 1111414

Other (OTH) AF: 0.00 AC: 0 AN: 60328

GnomAD4 genome AF: 0.00000659 AC: 1 AN: 151648 Hom.: 0 Cov.: 31 AF XY: 0.0000135 AC XY: 1 AN XY: 74012

African (AFR) AF: 0.0000242 AC: 1 AN: 41256

American (AMR) AF: 0.00 AC: 0 AN: 15206

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5172

South Asian (SAS) AF: 0.00 AC: 0 AN: 4794

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10558

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67890

Other (OTH) AF: 0.00 AC: 0 AN: 2076

Bravo AF: 0.0000113

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Benign	-0.21
CADD	Benign	0.0090
DEOGEN2	Benign	0.023	T;T;.
FATHMM_MKL	Benign	0.0019	N
LIST_S2	Benign	0.37	T;.;T
M_CAP	Benign	0.027	D
MetaRNN	Benign	0.17	T;T;T
MetaSVM	Uncertain	0.14	D
MutationAssessor	Benign	0.90	L;L;.
PhyloP100		-0.86
PrimateAI	Uncertain	0.50	T
PROVEAN	Benign	-0.29	.;N;.
REVEL	Benign	0.24
Sift	Pathogenic	0.0	.;D;.
Sift4G	Benign	0.072	T;T;T
Polyphen		0.22	B;B;.
Vest4		0.31
MutPred		0.48		Loss of catalytic residue at V244 (P = 0.0084);Loss of catalytic residue at V244 (P = 0.0084);.;
MVP		0.74
MPC		0.060
ClinPred		0.038	T
GERP RS		-3.0

Splicing

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

Other links and lift over

dbSNP: rs151218732; hg19: chrX-1314931;