Genetic Variant NM_004379.5:c.*6215A>G (chr2-207603273-A-G) – ACMG Classification: Benign (-10 pts)

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_ModerateBA1

The NM_004379.5(CREB1):c.*6215A>G variant causes a 3 prime UTR change. The variant allele was found at a frequency of 0.846 in 221,212 control chromosomes in the GnomAD database, including 79,600 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 0.84 ( 54441 hom., cov: 32)

Exomes 𝑓: 0.85 ( 25159 hom. )

Consequence

CREB1
NM_004379.5 3_prime_UTR

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 3.67

Publications

28 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:

METTL21A (HGNC:30476): (methyltransferase 21A, HSPA lysine) Enables ATPase binding activity; Hsp70 protein binding activity; and protein-lysine N-methyltransferase activity. Involved in peptidyl-lysine methylation. Part of protein-containing complex. [provided by Alliance of Genome Resources, Apr 2022]

METTL21A links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -10 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.38).

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.976 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CREB1	NM_004379.5 link	c.*6215A>G		3_prime_UTR_variant	Exon 8 of 8	ENST00000353267.8	NP_004370.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CREB1	ENST00000353267.8 link	c.*6215A>G		3_prime_UTR_variant	Exon 8 of 8	1	NM_004379.5	ENSP00000236995.3

Frequencies

GnomAD3 genomes

AF:

0.844

AC:

128384

AN:

152082

Hom.:

54384

Cov.:

show subpopulations

Gnomad AFR

AF:

0.866

Gnomad AMI

AF:

0.735

Gnomad AMR

AF:

0.867

Gnomad ASJ

AF:

0.813

Gnomad EAS

AF:

0.999

Gnomad SAS

AF:

0.939

Gnomad FIN

AF:

0.861

Gnomad MID

AF:

0.791

Gnomad NFE

AF:

0.808

Gnomad OTH

AF:

0.843

GnomAD4 exome

AF:

0.851

AC:

58709

AN:

69012

Hom.:

25159

Cov.:

AF XY:

0.849

AC XY:

27080

AN XY:

31908

show subpopulations

African (AFR)

AF:

0.879

AC:

2862

AN:

3256

American (AMR)

AF:

0.883

AC:

1893

AN:

2144

Ashkenazi Jewish (ASJ)

AF:

0.807

AC:

3563

AN:

4414

East Asian (EAS)

AF:

1.00

AC:

9803

AN:

9806

South Asian (SAS)

AF:

0.928

AC:

551

AN:

594

European-Finnish (FIN)

AF:

0.740

AC:

AN:

Middle Eastern (MID)

AF:

0.830

AC:

352

AN:

424

European-Non Finnish (NFE)

AF:

0.816

AC:

34758

AN:

42582

Other (OTH)

AF:

0.852

AC:

4890

AN:

5742

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.496

Heterozygous variant carriers

419

839

1258

1678

2097

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

116

232

348

464

580

<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:

0.844

AC:

128500

AN:

152200

Hom.:

54441

Cov.:

AF XY:

0.849

AC XY:

63202

AN XY:

74420

show subpopulations

African (AFR)

AF:

0.866

AC:

35962

AN:

41520

American (AMR)

AF:

0.867

AC:

13252

AN:

15282

Ashkenazi Jewish (ASJ)

AF:

0.813

AC:

2824

AN:

3472

East Asian (EAS)

AF:

0.999

AC:

5189

AN:

5194

South Asian (SAS)

AF:

0.939

AC:

4533

AN:

4826

European-Finnish (FIN)

AF:

0.861

AC:

9117

AN:

10594

Middle Eastern (MID)

AF:

0.793

AC:

233

AN:

294

European-Non Finnish (NFE)

AF:

0.808

AC:

54936

AN:

67994

Other (OTH)

AF:

0.845

AC:

1784

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

1034

2068

3101

4135

5169

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

890

1780

2670

3560

4450

<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:

0.824

Hom.:

58346

Bravo

AF:

0.848

Asia WGS

AF:

0.962

AC:

3341

AN:

3472

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.38

CADD

Benign

(source)

DANN

Benign

0.91

PhyloP100

3.7

Mutation Taster

=95/5

polymorphism (auto)

(source)

Splicing

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