X-1196817-C-T

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 1P and 12B. PP2 BP4_Strong BA1

The NM_022148.4(CRLF2):​c.730G>A​(p.Val244Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0636 in 1,612,362 control chromosomes in the GnomAD database, including 3,672 homozygotes. There are 50,786 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 9/13 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as not provided (no stars).

• Frequency:
  • Genomes: 𝑓 0.073 (459 hom., 5396 hem., cov: 31)
  • Exomes 𝑓: 0.063 (3213 hom. 45390 hem.)
• Consequence: CRLF2 NM_022148.4 missense
• Clinical Significance: not provided no classification provided O:1
• Conservation: PhyloP100: -0.856
• Publications: 1 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 -11 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=0.0023950338).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0947 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CRLF2	NM_022148.4	c.730G>A	p.Val244Met	missense_variant	Exon 6 of 8	ENST00000400841.8	NP_071431.2
CRLF2	NM_001012288.3	c.394G>A	p.Val132Met	missense_variant	Exon 5 of 7		NP_001012288.2
CRLF2	XM_011546181.3	c.727G>A	p.Val243Met	missense_variant	Exon 6 of 8		XP_011544483.1
CRLF2	NR_110830.2	n.924G>A		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>A	p.Val244Met	missense_variant	Exon 6 of 8	1	NM_022148.4	ENSP00000383641.3
CRLF2	ENST00000381567.8	c.394G>A	p.Val132Met	missense_variant	Exon 5 of 7	1		ENSP00000370979.4
CRLF2	ENST00000467626.6	n.*210G>A		non_coding_transcript_exon_variant	Exon 6 of 8	5		ENSP00000485269.1
CRLF2	ENST00000467626.6	n.*210G>A		3_prime_UTR_variant	Exon 6 of 8	5		ENSP00000485269.1

Frequencies

GnomAD3 genomes AF: 0.0726 AC: 11000 AN: 151616 Hom.: 458 Cov.: 31

Gnomad AFR AF: 0.0972

Gnomad AMI AF: 0.0680

Gnomad AMR AF: 0.0554

Gnomad ASJ AF: 0.0603

Gnomad EAS AF: 0.000773

Gnomad SAS AF: 0.0471

Gnomad FIN AF: 0.0930

Gnomad MID AF: 0.0918

Gnomad NFE AF: 0.0661

Gnomad OTH AF: 0.0718

GnomAD4 exome AF: 0.0627 AC: 91610 AN: 1460628 Hom.: 3213 Cov.: 32 AF XY: 0.0625 AC XY: 45390 AN XY: 726562

African (AFR) AF: 0.0948 AC: 3169 AN: 33436

American (AMR) AF: 0.0357 AC: 1593 AN: 44668

Ashkenazi Jewish (ASJ) AF: 0.0573 AC: 1497 AN: 26114

East Asian (EAS) AF: 0.000353 AC: 14 AN: 39670

South Asian (SAS) AF: 0.0501 AC: 4315 AN: 86162

European-Finnish (FIN) AF: 0.0877 AC: 4681 AN: 53376

Middle Eastern (MID) AF: 0.0829 AC: 477 AN: 5752

European-Non Finnish (NFE) AF: 0.0649 AC: 72076 AN: 1111136

Other (OTH) AF: 0.0628 AC: 3788 AN: 60314

GnomAD4 genome AF: 0.0726 AC: 11010 AN: 151734 Hom.: 459 Cov.: 31 AF XY: 0.0728 AC XY: 5396 AN XY: 74120

African (AFR) AF: 0.0972 AC: 4020 AN: 41366

American (AMR) AF: 0.0553 AC: 842 AN: 15222

Ashkenazi Jewish (ASJ) AF: 0.0603 AC: 209 AN: 3466

East Asian (EAS) AF: 0.000775 AC: 4 AN: 5160

South Asian (SAS) AF: 0.0474 AC: 227 AN: 4790

European-Finnish (FIN) AF: 0.0930 AC: 981 AN: 10554

Middle Eastern (MID) AF: 0.0918 AC: 27 AN: 294

European-Non Finnish (NFE) AF: 0.0661 AC: 4489 AN: 67872

Other (OTH) AF: 0.0710 AC: 149 AN: 2098

Bravo AF: 0.0714

TwinsUK AF: 0.0515 AC: 191

ALSPAC AF: 0.0677 AC: 261

ESP6500AA AF: 0.0894 AC: 335

ESP6500EA AF: 0.0675 AC: 553

ExAC AF: 0.0614 AC: 7414

ClinVar

Significance: not provided

Submissions summary: Other:1

Revision: no classification provided

Submissions by phenotype

not specified Other:1

Sep 19, 2013

ITMI

Significance: not provided

Review Status: no classification provided

Collection Method: reference population

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.33	T
BayesDel_noAF	Benign	-0.17
CADD	Benign	0.61
DEOGEN2	Benign	0.050	T;T;.
FATHMM_MKL	Benign	0.0011	N
LIST_S2	Benign	0.45	T;.;T
MetaRNN	Benign	0.0024	T;T;T
MetaSVM	Uncertain	0.0092	D
MutationAssessor	Benign	1.0	L;L;.
PhyloP100		-0.86
PrimateAI	Uncertain	0.51	T
PROVEAN	Benign	-0.48	.;N;.
REVEL	Uncertain	0.36
Sift	Pathogenic	0.0	.;D;.
Sift4G	Uncertain	0.017	D;D;D
Polyphen		0.98	D;D;.
Vest4		0.29
MPC		0.15
ClinPred		0.028	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;