2-207555724-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 3P and 2B. PM2 PP2 BP4_Moderate

The NM_004379.5(CREB1):c.89A>G(p.Gln30Arg) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,460,996 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: CREB1 NM_004379.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.97

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

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, CREB1
• BP4: Computational evidence support a benign effect (MetaRNN=0.20185277).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CREB1	NM_004379.5	c.89A>G	p.Gln30Arg	missense_variant	2/8	ENST00000353267.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CREB1	ENST00000353267.8	c.89A>G	p.Gln30Arg	missense_variant	2/8	1	NM_004379.5	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1460996 Hom.: 0 Cov.: 29 AF XY: 0.00 AC XY: 0 AN XY: 726810

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000329 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

May 08, 2023

The c.89A>G (p.Q30R) alteration is located in exon 2 (coding exon 1) of the CREB1 gene. This alteration results from a A to G substitution at nucleotide position 89, causing the glutamine (Q) at amino acid position 30 to be replaced by an arginine (R). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	0.0078	T
BayesDel_noAF	Benign	-0.23
Cadd	Uncertain	24
Dann	Uncertain	0.99
Eigen	Benign	-0.042
Eigen_PC	Benign	0.12
FATHMM_MKL	Uncertain	0.93	D
M_CAP	Benign	0.031	D
MetaRNN	Benign	0.20	T;T;T;T;T;T
MetaSVM	Benign	-0.57	T
MutationAssessor	Benign	1.2	L;L;L;.;.;.
MutationTaster	Benign	0.94	D;D;D;D;D
PrimateAI	Uncertain	0.66	T
PROVEAN	Benign	-0.67	N;N;N;N;N;N
REVEL	Benign	0.054
Sift	Uncertain	0.011	D;D;D;D;D;D
Sift4G	Benign	0.61	T;T;T;T;T;D
Polyphen		0.0	.;B;.;.;.;.
Vest4		0.40
MVP		0.71
MPC		0.11
ClinPred		0.45	T
GERP RS		4.6
Varity_R		0.15
gMVP		0.71

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

LitVar

Other links and lift over

dbSNP: rs1327500450; hg19: chr2-208420448;