Genetic Variant CREB1:c.-8-5011C>T (chr2-207550617-C-T) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_004379.5(CREB1):c.-8-5011C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.892 in 152,168 control chromosomes in the GnomAD database, including 61,753 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 0.89 ( 61753 hom., cov: 31)

Failed GnomAD Quality Control

Consequence

CREB1
NM_004379.5 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.223

Publications

1 publications found

Variant links:

Genes affected

CREB1 (HGNC:2345): (cAMP responsive element binding protein 1) This gene encodes a transcription factor that is a member of the leucine zipper family of DNA binding proteins. This protein binds as a homodimer to the cAMP-responsive element, an octameric palindrome. The protein is phosphorylated by several protein kinases, and induces transcription of genes in response to hormonal stimulation of the cAMP pathway. Alternate splicing of this gene results in several transcript variants encoding different isoforms. [provided by RefSeq, Mar 2016]

CREB1 links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.91).

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.977 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004379.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
CREB1	NM_004379.5	MANE Select	c.-8-5011C>T	intron	N/A	NP_004370.1	Q53X93
CREB1	NM_001371426.1		c.-8-5011C>T	intron	N/A	NP_001358355.1	P16220-1
CREB1	NM_134442.5		c.-8-5011C>T	intron	N/A	NP_604391.1	Q5U0J5

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
CREB1	ENST00000353267.8	TSL:1 MANE Select	c.-8-5011C>T	intron	N/A	ENSP00000236995.3	P16220-2
CREB1	ENST00000432329.6	TSL:1	c.-8-5011C>T	intron	N/A	ENSP00000387699.2	P16220-1
CREB1	ENST00000915136.1		c.-75-2688C>T	intron	N/A	ENSP00000585195.1

Frequencies

GnomAD3 genomes

AF:

0.893

AC:

135716

AN:

152050

Hom.:

61718

Cov.:

show subpopulations

Gnomad AFR

AF:

0.697

Gnomad AMI

AF:

0.814

Gnomad AMR

AF:

0.939

Gnomad ASJ

AF:

0.937

Gnomad EAS

AF:

0.999

Gnomad SAS

AF:

0.995

Gnomad FIN

AF:

0.975

Gnomad MID

AF:

0.940

Gnomad NFE

AF:

0.971

Gnomad OTH

AF:

0.899

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AC:

AN:

Hom.:

Cov.:

AC XY:

AN XY:

African (AFR)

AC:

AN:

American (AMR)

AC:

AN:

Ashkenazi Jewish (ASJ)

AC:

AN:

East Asian (EAS)

AC:

AN:

South Asian (SAS)

AC:

AN:

European-Finnish (FIN)

AC:

AN:

Middle Eastern (MID)

AC:

AN:

European-Non Finnish (NFE)

AC:

AN:

Other (OTH)

AC:

AN:

GnomAD4 genome

AF:

0.892

AC:

135809

AN:

152168

Hom.:

61753

Cov.:

AF XY:

0.895

AC XY:

66551

AN XY:

74396

show subpopulations

African (AFR)

AF:

0.697

AC:

28893

AN:

41442

American (AMR)

AF:

0.939

AC:

14356

AN:

15286

Ashkenazi Jewish (ASJ)

AF:

0.937

AC:

3252

AN:

3472

East Asian (EAS)

AF:

0.999

AC:

5187

AN:

5190

South Asian (SAS)

AF:

0.995

AC:

4800

AN:

4824

European-Finnish (FIN)

AF:

0.975

AC:

10342

AN:

10610

Middle Eastern (MID)

AF:

0.935

AC:

275

AN:

294

European-Non Finnish (NFE)

AF:

0.971

AC:

66061

AN:

68026

Other (OTH)

AF:

0.900

AC:

1901

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.506

Heterozygous variant carriers

635

1269

1904

2538

3173

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

894

1788

2682

3576

4470

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.940

Hom.:

13715

Bravo

AF:

0.882

Asia WGS

AF:

0.977

AC:

3397

AN:

3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.91

CADD

Benign

2.2

(source)

DANN

Benign

0.47

PhyloP100

-0.22

PromoterAI

-0.0017

Neutral

(source)

Mutation Taster

=100/0

polymorphism (auto)

(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