Genetic Variant CREB1:c.-8-5215A>G (chr2-207550413-A-G) – 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.-8-5215A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.879 in 150,226 control chromosomes in the GnomAD database, including 59,640 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 0.88 ( 59640 hom., cov: 24)

Failed GnomAD Quality Control

Consequence

CREB1
NM_004379.5 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.183

Publications

3 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=-0.85).

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
CREB1	NM_004379.5	MANE Select	c.-8-5215A>G	intron	N/A	NP_004370.1
CREB1	NM_001371426.1		c.-8-5215A>G	intron	N/A	NP_001358355.1
CREB1	NM_134442.5		c.-8-5215A>G	intron	N/A	NP_604391.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein
CREB1	ENST00000353267.8	TSL:1 MANE Select	c.-8-5215A>G	intron	N/A	ENSP00000236995.3
CREB1	ENST00000432329.6	TSL:1	c.-8-5215A>G	intron	N/A	ENSP00000387699.2
CREB1	ENST00000414681.1	TSL:4	c.-191A>G	5_prime_UTR	Exon 1 of 3	ENSP00000404890.1

Frequencies

GnomAD3 genomes

AF:

0.879

AC:

132019

AN:

150116

Hom.:

59614

Cov.:

show subpopulations

Gnomad AFR

AF:

0.649

Gnomad AMI

AF:

0.813

Gnomad AMR

AF:

0.935

Gnomad ASJ

AF:

0.937

Gnomad EAS

AF:

0.999

Gnomad SAS

AF:

0.995

Gnomad FIN

AF:

0.974

Gnomad MID

AF:

0.940

Gnomad NFE

AF:

0.971

Gnomad OTH

AF:

0.891

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:

0.879

AC:

132092

AN:

150226

Hom.:

59640

Cov.:

AF XY:

0.882

AC XY:

64615

AN XY:

73290

show subpopulations

African (AFR)

AF:

0.649

AC:

26340

AN:

40594

American (AMR)

AF:

0.935

AC:

14085

AN:

15070

Ashkenazi Jewish (ASJ)

AF:

0.937

AC:

3245

AN:

3464

East Asian (EAS)

AF:

0.999

AC:

5127

AN:

5130

South Asian (SAS)

AF:

0.995

AC:

4727

AN:

4752

European-Finnish (FIN)

AF:

0.974

AC:

9878

AN:

10138

Middle Eastern (MID)

AF:

0.935

AC:

275

AN:

294

European-Non Finnish (NFE)

AF:

0.971

AC:

65827

AN:

67802

Other (OTH)

AF:

0.892

AC:

1851

AN:

2076

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

605

1210

1816

2421

3026

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

880

1760

2640

3520

4400

<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:

0.945

Hom.:

8893

Bravo

AF:

0.866

Asia WGS

AF:

0.975

AC:

3389

AN:

3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.85

CADD

Benign

2.7

(source)

DANN

Benign

0.55

PhyloP100

0.18

PromoterAI

0.020

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