rs200254974

Variant names:

• chrX-1198571-C-T
• rs200254974
• NM_022148.4:c.637G>A

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 1P and 8B. PP2 BP4_Strong BS2

The NM_022148.4(CRLF2):​c.637G>A​(p.Glu213Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000356 in 1,613,642 control chromosomes in the GnomAD database, including 4 homozygotes. There are 371 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 13/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as not provided (no stars).

• Frequency:
  • Genomes: 𝑓 0.00023 (0 hom., 20 hem., cov: 30)
  • Exomes 𝑓: 0.00037 (4 hom. 351 hem.)
• Consequence: CRLF2 NM_022148.4 missense
• Clinical Significance: not provided no classification provided O:1
• Conservation: PhyloP100: -1.19
• 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: Benign. The variant received -7 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=0.009222776).
• BS2: High Hemizygotes in GnomAd4 at 20 gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_022148.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CRLF2	NM_022148.4	MANE Select	c.637G>A	p.Glu213Lys	missense	Exon 5 of 8	NP_071431.2
	CRLF2	NM_001012288.3		c.301G>A	p.Glu101Lys	missense	Exon 4 of 7	NP_001012288.2
	CRLF2	NR_110830.2		n.840+230G>A		intron	N/A

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CRLF2	ENST00000400841.8	TSL:1 MANE Select	c.637G>A	p.Glu213Lys	missense	Exon 5 of 8	ENSP00000383641.3
	CRLF2	ENST00000381567.8	TSL:1	c.301G>A	p.Glu101Lys	missense	Exon 4 of 7	ENSP00000370979.4
	CRLF2	ENST00000467626.6	TSL:5	n.*126+230G>A		intron	N/A	ENSP00000485269.1

Frequencies

GnomAD3 genomes AF: 0.000237 AC: 36 AN: 152070 Hom.: 0 Cov.: 30

Gnomad AFR AF: 0.0000242

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000590

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000191

Gnomad OTH AF: 0.000479

GnomAD2 exomes AF: 0.000643 AC: 160 AN: 248818 AF XY: 0.000837

Gnomad AFR exome AF: 0.0000645

Gnomad AMR exome AF: 0.000695

Gnomad ASJ exome AF: 0.000995

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000266

Gnomad OTH exome AF: 0.000662

GnomAD4 exome AF: 0.000369 AC: 540 AN: 1461454 Hom.: 4 Cov.: 39 AF XY: 0.000483 AC XY: 351 AN XY: 727016

African (AFR) AF: 0.000388 AC: 13 AN: 33472

American (AMR) AF: 0.000671 AC: 30 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.000804 AC: 21 AN: 26132

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39698

South Asian (SAS) AF: 0.00299 AC: 258 AN: 86246

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53402

Middle Eastern (MID) AF: 0.00364 AC: 21 AN: 5762

European-Non Finnish (NFE) AF: 0.000157 AC: 175 AN: 1111672

Other (OTH) AF: 0.000348 AC: 21 AN: 60354

GnomAD4 genome AF: 0.000230 AC: 35 AN: 152188 Hom.: 0 Cov.: 30 AF XY: 0.000269 AC XY: 20 AN XY: 74398

African (AFR) AF: 0.0000241 AC: 1 AN: 41518

American (AMR) AF: 0.000589 AC: 9 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.000288 AC: 1 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5152

South Asian (SAS) AF: 0.00207 AC: 10 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000191 AC: 13 AN: 68012

Other (OTH) AF: 0.000474 AC: 1 AN: 2108

Bravo AF: 0.000208

ESP6500AA AF: 0.000471 AC: 2

ESP6500EA AF: 0.000237 AC: 2

ExAC AF: 0.000570 AC: 69

EpiCase AF: 0.000545

EpiControl AF: 0.000652

ClinVar

ClinVar submissions as Germline

Significance: not provided

Revision: no classification provided

Pathogenic	VUS	Benign	Condition
-	-	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.29	T
BayesDel_noAF	Benign	-0.19
CADD	Benign	0.32
DANN	Benign	0.30
DEOGEN2	Benign	0.021	T
FATHMM_MKL	Benign	0.0017	N
LIST_S2	Benign	0.50	T
M_CAP	Uncertain	0.10	D
MetaRNN	Benign	0.0092	T
MetaSVM	Uncertain	0.42	D
MutationAssessor	Benign	1.8	L
PhyloP100		-1.2
PrimateAI	Uncertain	0.62	T
PROVEAN	Benign	-0.13	N
REVEL	Benign	0.27
Sift	Benign	0.58	T
Sift4G	Benign	0.55	T
Polyphen		0.033	B
Vest4		0.13
MVP		0.81
MPC		0.079
ClinPred		0.0071	T
GERP RS		-3.8
Varity_R		0.076

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs200254974; hg19: chrX-1317428; COSMIC: COSV107500125;