Genetic Variant CREBL2:p.Gln81Glu (chr12-12637597-C-G) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2BP4

The NM_001310.4(CREBL2):c.241C>G(p.Gln81Glu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000688 in 1,453,440 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 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. Q81K) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 31)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

CREBL2
NM_001310.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 7.49

Publications

0 publications found

Variant links:

Genes affected

CREBL2 (HGNC:2350): (cAMP responsive element binding protein like 2) cAMP response element (CRE)-binding protein-like-2 (CREBL2) was identified in a search to find genes in a commonly deleted region on chromosome 12p13 flanked by ETV6 and CDKN1B genes, frequently associated with hematopoietic malignancies, as well as breast, non-small-cell lung and ovarian cancers. CREBL2 shares a 41% identity with CRE-binding protein (CREB) over a 48-base long region which encodes the bZip domain of CREB. The bZip domain consists of about 30 amino acids rich in basic residues involved in DNA binding, followed by a leucine zipper motif involved in protein dimerization. This suggests that CREBL2 encodes a protein with DNA binding capabilities. The occurance of CREBL2 deletion in malignancy suggests that CREBL2 may act as a tumor suppressor gene. [provided by RefSeq, Jul 2008]

CREBL2 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.2905161).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001310.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CREBL2	NM_001310.4	MANE Select	c.241C>G	p.Gln81Glu	missense	Exon 3 of 4	NP_001301.1	O60519

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CREBL2	ENST00000228865.3	TSL:1 MANE Select	c.241C>G	p.Gln81Glu	missense	Exon 3 of 4	ENSP00000228865.2	O60519
CREBL2	ENST00000965829.1		c.241C>G	p.Gln81Glu	missense	Exon 3 of 5	ENSP00000635888.1
CREBL2	ENST00000893303.1		c.43C>G	p.Gln15Glu	missense	Exon 2 of 3	ENSP00000563362.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.88e-7

AC:

AN:

1453440

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

723166

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33310

American (AMR)

AF:

0.00

AC:

AN:

44542

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25822

East Asian (EAS)

AF:

0.00

AC:

AN:

39612

South Asian (SAS)

AF:

0.00

AC:

AN:

84942

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52928

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5710

European-Non Finnish (NFE)

AF:

9.04e-7

AC:

AN:

1106662

Other (OTH)

AF:

0.00

AC:

AN:

59912

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<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

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Uncertain

0.013

BayesDel_noAF

Benign

-0.22

CADD

Benign

(source)

DANN

Benign

0.96

DEOGEN2

Benign

0.041

Eigen

Benign

0.18

Eigen_PC

Uncertain

0.39

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.93

M_CAP

Benign

0.0062

MetaRNN

Benign

0.29

MetaSVM

Benign

-0.94

MutationAssessor

Benign

0.0

PhyloP100

7.5

PrimateAI

Uncertain

0.73

PROVEAN

Benign

-0.34

REVEL

Benign

0.17

Sift

Benign

0.66

Sift4G

Benign

0.97

Polyphen

0.15

Vest4

0.68

MutPred

0.25

Gain of catalytic residue at M79 (P = 0.0055)

MVP

0.11

MPC

1.2

ClinPred

0.87

GERP RS

6.0

Varity_R

0.14

gMVP

0.65

Mutation Taster

=59/41

polymorphism

(source)

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over