2-207560248-C-T

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_004379.5(CREB1):​c.137C>T​(p.Ala46Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000095 in 1,611,366 control chromosomes in the GnomAD database, including 1 homozygotes. 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. A46G) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00012 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000092 (1 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: Benign. The variant received -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.011686832).
• BS2: High AC in GnomAd4 at 19 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>T	p.Ala46Val	missense	Exon 3 of 8	NP_004370.1	Q53X93
	CREB1	NM_001371426.1		c.137C>T	p.Ala46Val	missense	Exon 3 of 9	NP_001358355.1	P16220-1
	CREB1	NM_134442.5		c.137C>T	p.Ala46Val	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>T	p.Ala46Val	missense	Exon 3 of 8	ENSP00000236995.3	P16220-2
	CREB1	ENST00000432329.6	TSL:1	c.137C>T	p.Ala46Val	missense	Exon 3 of 9	ENSP00000387699.2	P16220-1
	CREB1	ENST00000915136.1		c.137C>T	p.Ala46Val	missense	Exon 4 of 10	ENSP00000585195.1

Frequencies

GnomAD3 genomes AF: 0.000125 AC: 19 AN: 152062 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00462

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000200 AC: 50 AN: 250358 AF XY: 0.000192

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000873

Gnomad ASJ exome AF: 0.00379

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000796

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000918 AC: 134 AN: 1459304 Hom.: 1 Cov.: 30 AF XY: 0.0000937 AC XY: 68 AN XY: 725678

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

American (AMR) AF: 0.0000449 AC: 2 AN: 44526

Ashkenazi Jewish (ASJ) AF: 0.00326 AC: 85 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: 0.0000225 AC: 25 AN: 1110216

Other (OTH) AF: 0.000365 AC: 22 AN: 60290

GnomAD4 genome AF: 0.000125 AC: 19 AN: 152062 Hom.: 0 Cov.: 32 AF XY: 0.000135 AC XY: 10 AN XY: 74260

African (AFR) AF: 0.00 AC: 0 AN: 41398

American (AMR) AF: 0.00 AC: 0 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.00462 AC: 16 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.00 AC: 0 AN: 4814

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10600

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000441 AC: 3 AN: 68016

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.000254 Hom.: 0

Bravo AF: 0.0000982

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.000140 AC: 17

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	0.084
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Benign	-0.28
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.41	T
Eigen	Benign	-0.32
Eigen_PC	Benign	-0.11
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Uncertain	0.91	D
M_CAP	Benign	0.023	T
MetaRNN	Benign	0.012	T
MetaSVM	Benign	-0.82	T
MutationAssessor	Benign	0.20	N
PhyloP100		2.1
PrimateAI	Uncertain	0.71	T
PROVEAN	Benign	-0.24	N
REVEL	Benign	0.065
Sift	Benign	0.70	T
Sift4G	Benign	0.62	T
Polyphen		0.0010	B
Vest4		0.25
MVP		0.54
MPC		0.097
ClinPred		0.037	T
GERP RS		4.5
Varity_R		0.18
gMVP		0.35
Mutation Taster		=69/31	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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;