12-12635933-C-T

Variant names:

• chr12-12635933-C-T
• NM_001310.4:c.172C>T

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP5_Moderate

The NM_001310.4(CREBL2):​c.172C>T​(p.Arg58*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: CREBL2 NM_001310.4 stop_gained
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 3.27
• Publications: 0 publications found

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]

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 12-12635933-C-T is Pathogenic according to our data. Variant chr12-12635933-C-T is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 3065406.Status of the report is criteria_provided_single_submitter, 1 stars.

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.172C>T	p.Arg58*	stop_gained	Exon 2 of 4	NP_001301.1	O60519

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CREBL2	ENST00000228865.3	TSL:1 MANE Select	c.172C>T	p.Arg58*	stop_gained	Exon 2 of 4	ENSP00000228865.2	O60519
	CREBL2	ENST00000965829.1		c.172C>T	p.Arg58*	stop_gained	Exon 2 of 5	ENSP00000635888.1
	CREBL2	ENST00000893303.1		c.16-1637C>T		intron	N/A	ENSP00000563362.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Likely pathogenic

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.57	D
BayesDel_noAF	Pathogenic	0.59
CADD	Pathogenic	37
DANN	Uncertain	1.0
Eigen	Uncertain	0.60
Eigen_PC	Uncertain	0.44
FATHMM_MKL	Uncertain	0.90	D
PhyloP100		3.3
Vest4		0.40
GERP RS		2.5
Mutation Taster		=17/183	disease causing (fs/PTC)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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

hg19: chr12-12788867; COSMIC: COSV99963606;