NM_022148.4:c.406G>A

Variant names:

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 1P and 9B. PP2BP4_StrongBS1_SupportingBS2

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. 12/17 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as not provided (no stars).

Frequency

Genomes: 𝑓 0.019 ( 38 hom., 1356 hem., cov: 31)

Exomes 𝑓: 0.022 ( 429 hom. 15864 hem. )

Consequence

CRLF2
NM_022148.4 missense

Scores

Clinical Significance

not provided no classification provided O:1

Conservation

PhyloP100: 0.0690

Publications

0 publications found

Variant links:

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]

CRLF2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -8 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=0.0035479069).

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 the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

BS2

High Homozygotes in GnomAd4 at 38 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CRLF2	NM_022148.4 link	c.406G>A	p.Val136Met	missense_variant	Exon 4 of 8	ENST00000400841.8	NP_071431.2	Q9HC73-1D0E2W4
CRLF2	NM_001012288.3 link	c.70G>A	p.Val24Met	missense_variant	Exon 3 of 7		NP_001012288.2	Q9HC73-3
CRLF2	XM_011546181.3 link	c.403G>A	p.Val135Met	missense_variant	Exon 4 of 8		XP_011544483.1
CRLF2	NR_110830.2 link	n.418G>A		non_coding_transcript_exon_variant	Exon 4 of 8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
CRLF2	ENST00000400841.8 link	c.406G>A	p.Val136Met	missense_variant	Exon 4 of 8	1	NM_022148.4	ENSP00000383641.3	Q9HC73-1
CRLF2	ENST00000381567.8 link	c.70G>A	p.Val24Met	missense_variant	Exon 3 of 7	1		ENSP00000370979.4	Q9HC73-3
CRLF2	ENST00000467626.6 link	n.403G>A		non_coding_transcript_exon_variant	Exon 4 of 8	5		ENSP00000485269.1	A0A0C4DH06

Frequencies

GnomAD3 genomes

AF:

0.0194

AC:

2955

AN:

152132

Hom.:

Cov.:

show subpopulations

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

GnomAD2 exomes

AF:

0.0176

AC:

4374

AN:

248930

AF XY:

0.0175

show subpopulations

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 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.:

AF XY:

0.0218

AC XY:

15864

AN XY:

726934

show subpopulations

African (AFR)

AF:

0.0171

AC:

573

AN:

33470

American (AMR)

AF:

0.0103

AC:

460

AN:

44712

Ashkenazi Jewish (ASJ)

AF:

0.0646

AC:

1689

AN:

26126

East Asian (EAS)

AF:

0.0000504

AC:

AN:

39700

South Asian (SAS)

AF:

0.00275

AC:

237

AN:

86246

European-Finnish (FIN)

AF:

0.0130

AC:

695

AN:

53402

Middle Eastern (MID)

AF:

0.0224

AC:

129

AN:

5762

European-Non Finnish (NFE)

AF:

0.0245

AC:

27258

AN:

1111550

Other (OTH)

AF:

0.0228

AC:

1378

AN:

60342

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.462

Heterozygous variant carriers

1536

3072

4608

6144

7680

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1056

2112

3168

4224

5280

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0194

AC:

2957

AN:

152250

Hom.:

Cov.:

AF XY:

0.0182

AC XY:

1356

AN XY:

74436

show subpopulations

African (AFR)

AF:

0.0158

AC:

658

AN:

41536

American (AMR)

AF:

0.0159

AC:

243

AN:

15286

Ashkenazi Jewish (ASJ)

AF:

0.0686

AC:

238

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5186

South Asian (SAS)

AF:

0.00249

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.0114

AC:

121

AN:

10618

Middle Eastern (MID)

AF:

0.0306

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0231

AC:

1568

AN:

68008

Other (OTH)

AF:

0.0251

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.496

Heterozygous variant carriers

153

306

460

613

766

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

128

160

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Bravo

AF:

0.0209

TwinsUK

AF:

0.0267

AC:

ALSPAC

AF:

0.0252

AC:

ESP6500AA

AF:

0.0141

AC:

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

LINK: link

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

-0.48

BayesDel_noAF

Benign

-0.44

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.099

T;T;.

FATHMM_MKL

Benign

0.0011

LIST_S2

Benign

0.64

T;.;T

MetaRNN

Benign

0.0035

T;T;T

MetaSVM

Benign

-0.77

MutationAssessor

Benign

2.0

M;M;.

PhyloP100

0.069

PrimateAI

Uncertain

0.71

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

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over