chr12-12643938-T-C

Variant names:

• chr12-12643938-T-C
• rs4555
• NM_001310.4:c.*1940T>C

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001310.4(CREBL2):​c.*1940T>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.441 in 152,554 control chromosomes in the GnomAD database, including 16,727 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.44 (16648 hom., cov: 32)
  • Exomes 𝑓: 0.61 (79 hom.)
• Consequence: CREBL2 NM_001310.4 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.768

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

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.55).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.554 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CREBL2	NM_001310.4	c.*1940T>C		3_prime_UTR_variant	Exon 4 of 4	ENST00000228865.3	NP_001301.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CREBL2	ENST00000228865.3	c.*1940T>C		3_prime_UTR_variant	Exon 4 of 4	1	NM_001310.4	ENSP00000228865.2

Frequencies

GnomAD3 genomes AF: 0.441 AC: 67026 AN: 152002 Hom.: 16647 Cov.: 32

Gnomad AFR AF: 0.220

Gnomad AMI AF: 0.619

Gnomad AMR AF: 0.360

Gnomad ASJ AF: 0.543

Gnomad EAS AF: 0.431

Gnomad SAS AF: 0.439

Gnomad FIN AF: 0.625

Gnomad MID AF: 0.453

Gnomad NFE AF: 0.558

Gnomad OTH AF: 0.437

GnomAD4 exome AF: 0.611 AC: 264 AN: 432 Hom.: 79 Cov.: 0 AF XY: 0.646 AC XY: 168 AN XY: 260

Gnomad4 FIN exome AF: 0.613

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.750

GnomAD4 genome AF: 0.441 AC: 67036 AN: 152122 Hom.: 16648 Cov.: 32 AF XY: 0.443 AC XY: 32947 AN XY: 74372

Gnomad4 AFR AF: 0.220

Gnomad4 AMR AF: 0.359

Gnomad4 ASJ AF: 0.543

Gnomad4 EAS AF: 0.431

Gnomad4 SAS AF: 0.441

Gnomad4 FIN AF: 0.625

Gnomad4 NFE AF: 0.558

Gnomad4 OTH AF: 0.433

Alfa AF: 0.533 Hom.: 25828

Bravo AF: 0.409

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.55
CADD	Benign	11
DANN	Benign	0.86

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: rs4555; hg19: chr12-12796872; COSMIC: COSV57429320;