Genetic Variant NM_004379.5:c.362+59A>G (chr2-207567622-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.362+59A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0268 in 1,211,500 control chromosomes in the GnomAD database, including 585 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 0.038 ( 146 hom., cov: 32)

Exomes 𝑓: 0.025 ( 439 hom. )

Consequence

CREB1
NM_004379.5 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.372

Publications

7 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=-0.78).

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0604 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CREB1	NM_004379.5 link	c.362+59A>G		intron_variant	Intron 4 of 7	ENST00000353267.8	NP_004370.1	P16220-2Q53X93

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CREB1	ENST00000353267.8 link	c.362+59A>G		intron_variant	Intron 4 of 7	1	NM_004379.5	ENSP00000236995.3		P16220-2

Frequencies

GnomAD3 genomes

AF:

0.0379

AC:

5765

AN:

152106

Hom.:

145

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0625

Gnomad AMI

AF:

0.184

Gnomad AMR

AF:

0.0331

Gnomad ASJ

AF:

0.0631

Gnomad EAS

AF:

0.000577

Gnomad SAS

AF:

0.00373

Gnomad FIN

AF:

0.0256

Gnomad MID

AF:

0.0443

Gnomad NFE

AF:

0.0276

Gnomad OTH

AF:

0.0465

GnomAD4 exome

AF:

0.0252

AC:

26686

AN:

1059276

Hom.:

439

Cov.:

AF XY:

0.0247

AC XY:

13404

AN XY:

543448

show subpopulations

African (AFR)

AF:

0.0607

AC:

1514

AN:

24934

American (AMR)

AF:

0.0228

AC:

936

AN:

41074

Ashkenazi Jewish (ASJ)

AF:

0.0525

AC:

1199

AN:

22822

East Asian (EAS)

AF:

0.0000548

AC:

AN:

36472

South Asian (SAS)

AF:

0.00439

AC:

330

AN:

75244

European-Finnish (FIN)

AF:

0.0240

AC:

1214

AN:

50536

Middle Eastern (MID)

AF:

0.0279

AC:

138

AN:

4944

European-Non Finnish (NFE)

AF:

0.0263

AC:

19922

AN:

756590

Other (OTH)

AF:

0.0307

AC:

1431

AN:

46660

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

1221

2441

3662

4882

6103

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

630

1260

1890

2520

3150

<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

AF:

0.0379

AC:

5767

AN:

152224

Hom.:

146

Cov.:

AF XY:

0.0377

AC XY:

2803

AN XY:

74434

show subpopulations

African (AFR)

AF:

0.0624

AC:

2594

AN:

41560

American (AMR)

AF:

0.0330

AC:

505

AN:

15290

Ashkenazi Jewish (ASJ)

AF:

0.0631

AC:

219

AN:

3468

East Asian (EAS)

AF:

0.000579

AC:

AN:

5184

South Asian (SAS)

AF:

0.00373

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.0256

AC:

272

AN:

10624

Middle Eastern (MID)

AF:

0.0476

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0276

AC:

1878

AN:

67966

Other (OTH)

AF:

0.0461

AC:

AN:

2106

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

286

572

859

1145

1431

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

128

192

256

320

<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:

0.0332

Hom.:

Bravo

AF:

0.0394

Asia WGS

AF:

0.0100

AC:

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.78

CADD

Benign

6.5

(source)

DANN

Benign

0.83

PhyloP100

-0.37

Mutation Taster

=100/0

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over