X-1202479-C-T

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BS1_Supporting BS2

The NM_022148.4(CRLF2):c.406G>A(p.Val136Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0219 in 1,613,560 control chromosomes in the GnomAD database, including 467 homozygotes. There are 17,220 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 11/16 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as not provided (no stars). Another nucleotide change resulting in same amino acid change has been previously reported as Uncertain significancein ClinVar.

• Frequency:
  • Genomes: 𝑓 0.019 (38 hom., 1356 hem., cov: 31)
  • Exomes 𝑓: 0.022 (429 hom. 15864 hem.)
• Consequence: CRLF2 NM_022148.4 missense
• Clinical Significance: not provided no classification provided O:1
• 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 Benign. Variant got -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0035479069).
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0194 (2957/152250) while in subpopulation NFE AF= 0.0231 (1568/68008). AF 95% confidence interval is 0.0221. There are 38 homozygotes in gnomad4. There are 1356 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High Homozygotes in GnomAd at 38 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CRLF2	NM_022148.4	c.406G>A	p.Val136Met	missense_variant	4/8	ENST00000400841.8
CRLF2	NM_001012288.3	c.70G>A	p.Val24Met	missense_variant	3/7
CRLF2	XM_011546181.3	c.403G>A	p.Val135Met	missense_variant	4/8
CRLF2	NR_110830.2	n.418G>A		non_coding_transcript_exon_variant	4/8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CRLF2	ENST00000400841.8	c.406G>A	p.Val136Met	missense_variant	4/8	1	NM_022148.4	P1
CRLF2	ENST00000381567.8	c.70G>A	p.Val24Met	missense_variant	3/7	1
CRLF2	ENST00000467626.6	c.403G>A	p.Val135Met	missense_variant, NMD_transcript_variant	4/8	5

Frequencies

GnomAD3 genomes AF: 0.0194 AC: 2955 AN: 152132 Hom.: 38 Cov.: 31 AF XY: 0.0182 AC XY: 1355 AN XY: 74308

Gnomad AFR AF: 0.0158

Gnomad AMI AF: 0.0603

Gnomad AMR AF: 0.0160

Gnomad ASJ AF: 0.0686

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00248

Gnomad FIN AF: 0.0114

Gnomad MID AF: 0.0253

Gnomad NFE AF: 0.0231

Gnomad OTH AF: 0.0254

GnomAD3 exomes AF: 0.0176 AC: 4374 AN: 248930 Hom.: 59 AF XY: 0.0175 AC XY: 2369 AN XY: 135034

Gnomad AFR exome AF: 0.0154

Gnomad AMR exome AF: 0.00968

Gnomad ASJ exome AF: 0.0642

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00271

Gnomad FIN exome AF: 0.0129

Gnomad NFE exome AF: 0.0237

Gnomad OTH exome AF: 0.0212

GnomAD4 exome AF: 0.0222 AC: 32421 AN: 1461310 Hom.: 429 Cov.: 32 AF XY: 0.0218 AC XY: 15864 AN XY: 726934

Gnomad4 AFR exome AF: 0.0171

Gnomad4 AMR exome AF: 0.0103

Gnomad4 ASJ exome AF: 0.0646

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.00275

Gnomad4 FIN exome AF: 0.0130

Gnomad4 NFE exome AF: 0.0245

Gnomad4 OTH exome AF: 0.0228

GnomAD4 genome AF: 0.0194 AC: 2957 AN: 152250 Hom.: 38 Cov.: 31 AF XY: 0.0182 AC XY: 1356 AN XY: 74436

Gnomad4 AFR AF: 0.0158

Gnomad4 AMR AF: 0.0159

Gnomad4 ASJ AF: 0.0686

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00249

Gnomad4 FIN AF: 0.0114

Gnomad4 NFE AF: 0.0231

Gnomad4 OTH AF: 0.0251

Bravo AF: 0.0209

TwinsUK AF: 0.0267 AC: 99

ALSPAC AF: 0.0252 AC: 97

ESP6500AA AF: 0.0141 AC: 59

ESP6500EA AF: 0.0256 AC: 215

ExAC AF: 0.0176 AC: 2131

EpiCase AF: 0.0241

EpiControl AF: 0.0261

ClinVar

Significance: not provided

Submissions summary: Other:1

Revision: no classification provided

Submissions by phenotype

not specified Other:1

not provided, no classification provided

reference population

ITMI

Sep 19, 2013

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.48	T
BayesDel_noAF	Benign	-0.44
Cadd	Benign	15
Dann	Uncertain	0.99
DEOGEN2	Benign	0.099	T;T;.
FATHMM_MKL	Benign	0.0011	N
LIST_S2	Benign	0.64	T;.;T
MetaRNN	Benign	0.0035	T;T;T
MetaSVM	Benign	-0.77	T
MutationAssessor	Benign	2.0	M;M;.
MutationTaster	Benign	1.0	N;N
PrimateAI	Uncertain	0.71	T
PROVEAN	Benign	-0.54	N;N;.
REVEL	Benign	0.24
Sift	Uncertain	0.0020	D;D;.
Sift4G	Uncertain	0.0080	D;D;D
Polyphen		1.0	D;D;.
Vest4		0.13
MPC		0.38
ClinPred		0.034	T
GERP RS		0.32
Varity_R		0.10

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

LitVar

Other links and lift over

dbSNP: rs138899368; hg19: chrX-1321349; COSMIC: COSV67494150;