NM_004379.5:c.305A>G

Variant names:

• chr2-207567506-A-G
• rs387906617
• NM_004379.5:c.305A>G

Variant summary

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

The NM_004379.5(CREB1):​c.305A>G​(p.Asp102Gly) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: CREB1 NM_004379.5 missense
• Clinical Significance: Uncertain significance no assertion criteria provided U:1
• Conservation: PhyloP100: 9.22
• Publications: 3 publications found

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]

ACMG classification

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_004379.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CREB1	NM_004379.5	MANE Select	c.305A>G	p.Asp102Gly	missense	Exon 4 of 8	NP_004370.1
	CREB1	NM_001371426.1		c.347A>G	p.Asp116Gly	missense	Exon 5 of 9	NP_001358355.1
	CREB1	NM_134442.5		c.347A>G	p.Asp116Gly	missense	Exon 5 of 9	NP_604391.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CREB1	ENST00000353267.8	TSL:1 MANE Select	c.305A>G	p.Asp102Gly	missense	Exon 4 of 8	ENSP00000236995.3
	CREB1	ENST00000432329.6	TSL:1	c.347A>G	p.Asp116Gly	missense	Exon 5 of 9	ENSP00000387699.2
	CREB1	ENST00000915136.1		c.347A>G	p.Asp116Gly	missense	Exon 6 of 10	ENSP00000585195.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
-	1	-	Variant of unknown significance (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.70
BayesDel_addAF	Pathogenic	0.40	D
BayesDel_noAF	Pathogenic	0.33
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.83	D
Eigen	Uncertain	0.22
Eigen_PC	Uncertain	0.40
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.96	D
M_CAP	Uncertain	0.088	D
MetaRNN	Uncertain	0.74	D
MetaSVM	Uncertain	-0.15	T
MutationAssessor	Benign	1.4	L
PhyloP100		9.2
PrimateAI	Pathogenic	0.85	D
PROVEAN	Uncertain	-3.2	D
REVEL	Uncertain	0.62
Sift	Benign	0.12	T
Sift4G	Benign	0.078	T
Polyphen		0.24	B
Vest4		0.56
MutPred		0.44		Loss of helix (P = 0.0376)
MVP		0.99
MPC		1.9
ClinPred		0.93	D
GERP RS		5.5
Varity_R		0.55
gMVP		0.66
Mutation Taster		=4/96	disease causing

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

Other links and lift over

dbSNP: rs387906617; hg19: chr2-208432230; COSMIC: COSV100783588;