Genetic Variant CREB5:p.Arg152Gly (chr7-28570527-C-G) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_182898.4(CREB5):c.454C>G(p.Arg152Gly) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,538 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R152C) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 31)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

CREB5
NM_182898.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 5.43

Publications

0 publications found

Variant links:

Genes affected

CREB5 (HGNC:16844): (cAMP responsive element binding protein 5) The product of this gene belongs to the CRE (cAMP response element)-binding protein family. Members of this family contain zinc-finger and bZIP DNA-binding domains. The encoded protein specifically binds to CRE as a homodimer or a heterodimer with c-Jun or CRE-BP1, and functions as a CRE-dependent trans-activator. Alternatively spliced transcript variants encoding different isoforms have been identified. [provided by RefSeq, Jul 2008]

CREB5 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_182898.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CREB5	NM_182898.4	MANE Select	c.454C>G	p.Arg152Gly	missense	Exon 5 of 11	NP_878901.2	Q02930-1
CREB5	NM_004904.4		c.433C>G	p.Arg145Gly	missense	Exon 5 of 11	NP_004895.2	Q02930-2
CREB5	NM_182899.5		c.355C>G	p.Arg119Gly	missense	Exon 4 of 10	NP_878902.2	Q02930-3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CREB5	ENST00000357727.7	TSL:1 MANE Select	c.454C>G	p.Arg152Gly	missense	Exon 5 of 11	ENSP00000350359.2	Q02930-1
CREB5	ENST00000396300.6	TSL:1	c.433C>G	p.Arg145Gly	missense	Exon 5 of 11	ENSP00000379594.2	Q02930-2
CREB5	ENST00000396299.6	TSL:1	c.355C>G	p.Arg119Gly	missense	Exon 4 of 10	ENSP00000379593.2	Q02930-3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461538

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

727042

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33470

American (AMR)

AF:

0.00

AC:

AN:

44684

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26116

East Asian (EAS)

AF:

0.00

AC:

AN:

39696

South Asian (SAS)

AF:

0.00

AC:

AN:

86170

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53418

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

8.99e-7

AC:

AN:

1111830

Other (OTH)

AF:

0.00

AC:

AN:

60386

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<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

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.80

BayesDel_addAF

Pathogenic

0.26

BayesDel_noAF

Pathogenic

0.14

CADD

Uncertain

(source)

DANN

Uncertain

0.99

DEOGEN2

Pathogenic

0.85

Eigen

Pathogenic

0.79

Eigen_PC

Pathogenic

0.76

FATHMM_MKL

Uncertain

0.79

LIST_S2

Uncertain

0.92

M_CAP

Benign

0.078

MetaRNN

Uncertain

0.69

MetaSVM

Uncertain

0.019

MutationAssessor

Uncertain

2.3

PhyloP100

5.4

PrimateAI

Pathogenic

0.90

PROVEAN

Uncertain

-3.0

REVEL

Uncertain

0.42

Sift

Uncertain

0.0010

Sift4G

Benign

0.068

Polyphen

0.99

Vest4

0.78

MutPred

0.20

Gain of loop (P = 0.0502)

MVP

0.65

MPC

1.1

ClinPred

1.0

GERP RS

5.5

Varity_R

0.60

gMVP

0.77

Mutation Taster

=47/53

disease causing

(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