rs143117860

Variant names:

• chr2-207560248-C-G
• rs143117860
• NM_004379.5:c.137C>G

Your query was ambiguous. Multiple possible variants found:

• chr2-207560248-C-G
• chr2-207560248-C-T

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_004379.5(CREB1):​c.137C>G​(p.Ala46Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000178 in 1,459,306 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A46V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000018 (0 hom.)
• Consequence: CREB1 NM_004379.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.13
• Publications: 0 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: Likely_benign. The variant received -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.16700771).
• BS2: High AC in GnomAdExome4 at 26 AD gene.

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.137C>G	p.Ala46Gly	missense	Exon 3 of 8	NP_004370.1	Q53X93
	CREB1	NM_001371426.1		c.137C>G	p.Ala46Gly	missense	Exon 3 of 9	NP_001358355.1	P16220-1
	CREB1	NM_134442.5		c.137C>G	p.Ala46Gly	missense	Exon 3 of 9	NP_604391.1	Q5U0J5

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CREB1	ENST00000353267.8	TSL:1 MANE Select	c.137C>G	p.Ala46Gly	missense	Exon 3 of 8	ENSP00000236995.3	P16220-2
	CREB1	ENST00000432329.6	TSL:1	c.137C>G	p.Ala46Gly	missense	Exon 3 of 9	ENSP00000387699.2	P16220-1
	CREB1	ENST00000915136.1		c.137C>G	p.Ala46Gly	missense	Exon 4 of 10	ENSP00000585195.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.0000178 AC: 26 AN: 1459306 Hom.: 0 Cov.: 30 AF XY: 0.0000152 AC XY: 11 AN XY: 725680

African (AFR) AF: 0.00 AC: 0 AN: 33426

American (AMR) AF: 0.00 AC: 0 AN: 44526

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26052

East Asian (EAS) AF: 0.00 AC: 0 AN: 39638

South Asian (SAS) AF: 0.00 AC: 0 AN: 86058

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53348

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5750

European-Non Finnish (NFE) AF: 0.0000234 AC: 26 AN: 1110216

Other (OTH) AF: 0.00 AC: 0 AN: 60292

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.076
BayesDel_addAF	Benign	-0.049	T
BayesDel_noAF	Benign	-0.31
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.43	T
Eigen	Benign	-0.24
Eigen_PC	Benign	-0.042
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.85	D
M_CAP	Benign	0.027	D
MetaRNN	Benign	0.17	T
MetaSVM	Benign	-0.76	T
MutationAssessor	Benign	0.20	N
PhyloP100		2.1
PrimateAI	Uncertain	0.68	T
PROVEAN	Benign	-0.84	N
REVEL	Benign	0.062
Sift	Benign	0.35	T
Sift4G	Benign	0.50	T
Polyphen		0.0010	B
Vest4		0.33
MutPred		0.23		Gain of catalytic residue at A46 (P = 0.0155)
MVP		0.57
MPC		0.098
ClinPred		0.36	T
GERP RS		4.5
Varity_R		0.20
gMVP		0.30
Mutation Taster		=65/35	polymorphism

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: rs143117860; hg19: chr2-208424972;