2-207586064-C-T

Variant names:

• chr2-207586064-C-T
• rs2551645
• NM_004379.5:c.839+8409C>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_004379.5(CREB1):​c.839+8409C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.548 in 151,976 control chromosomes in the GnomAD database, including 24,459 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.55 (24459 hom., cov: 32)
• Consequence: CREB1 NM_004379.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.921
• Publications: 4 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]

METTL21A (HGNC:30476): (methyltransferase 21A, HSPA lysine) Enables ATPase binding activity; Hsp70 protein binding activity; and protein-lysine N-methyltransferase activity. Involved in peptidyl-lysine methylation. Part of protein-containing complex. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.97).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.644 is higher than 0.05.

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.839+8409C>T		intron	N/A	NP_004370.1	Q53X93
	CREB1	NM_001371426.1		c.881+8409C>T		intron	N/A	NP_001358355.1	P16220-1
	CREB1	NM_134442.5		c.881+8409C>T		intron	N/A	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.839+8409C>T		intron	N/A	ENSP00000236995.3	P16220-2
	CREB1	ENST00000432329.6	TSL:1	c.881+8409C>T		intron	N/A	ENSP00000387699.2	P16220-1
	METTL21A	ENST00000458426.5	TSL:1	c.260-3904G>A		intron	N/A	ENSP00000389684.1	Q8WXB1-2

Frequencies

GnomAD3 genomes AF: 0.548 AC: 83227 AN: 151858 Hom.: 24456 Cov.: 32

Gnomad AFR AF: 0.328

Gnomad AMI AF: 0.677

Gnomad AMR AF: 0.582

Gnomad ASJ AF: 0.675

Gnomad EAS AF: 0.638

Gnomad SAS AF: 0.486

Gnomad FIN AF: 0.625

Gnomad MID AF: 0.722

Gnomad NFE AF: 0.649

Gnomad OTH AF: 0.597

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.548 AC: 83255 AN: 151976 Hom.: 24459 Cov.: 32 AF XY: 0.547 AC XY: 40664 AN XY: 74280

African (AFR) AF: 0.327 AC: 13567 AN: 41440

American (AMR) AF: 0.582 AC: 8883 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.675 AC: 2342 AN: 3468

East Asian (EAS) AF: 0.639 AC: 3300 AN: 5168

South Asian (SAS) AF: 0.487 AC: 2344 AN: 4814

European-Finnish (FIN) AF: 0.625 AC: 6590 AN: 10540

Middle Eastern (MID) AF: 0.707 AC: 208 AN: 294

European-Non Finnish (NFE) AF: 0.650 AC: 44145 AN: 67966

Other (OTH) AF: 0.600 AC: 1263 AN: 2106

Alfa AF: 0.604 Hom.: 12597

Bravo AF: 0.533

Asia WGS AF: 0.540 AC: 1870 AN: 3470

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.97
CADD	Benign	0.96
DANN	Benign	0.31
PhyloP100		-0.92
Mutation Taster		=100/0	polymorphism (auto)

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: rs2551645; hg19: chr2-208450788; COSMIC: COSV107435611;