2-207575348-C-G

Variant names:

• chr2-207575348-C-G
• rs56020464
• NM_004379.5:c.582C>G

Variant summary

Our verdict is Benign. The variant received -15 ACMG points: 0P and 15B. BP4_Moderate BP6_Very_Strong BP7 BS2

The NM_004379.5(CREB1):​c.582C>G​(p.Thr194Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00446 in 1,614,092 control chromosomes in the GnomAD database, including 45 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0039 (2 hom., cov: 32)
  • Exomes 𝑓: 0.0045 (43 hom.)
• Consequence: CREB1 NM_004379.5 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.804
• 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: Benign. The variant received -15 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.4).
• BP6: Variant 2-207575348-C-G is Benign according to our data. Variant chr2-207575348-C-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 769581.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.804 with no splicing effect.
• BS2: High AC in GnomAd4 at 593 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.582C>G	p.Thr194Thr	synonymous	Exon 6 of 8	NP_004370.1	Q53X93
	CREB1	NM_001371426.1		c.624C>G	p.Thr208Thr	synonymous	Exon 7 of 9	NP_001358355.1	P16220-1
	CREB1	NM_134442.5		c.624C>G	p.Thr208Thr	synonymous	Exon 7 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.582C>G	p.Thr194Thr	synonymous	Exon 6 of 8	ENSP00000236995.3	P16220-2
	CREB1	ENST00000432329.6	TSL:1	c.624C>G	p.Thr208Thr	synonymous	Exon 7 of 9	ENSP00000387699.2	P16220-1
	CREB1	ENST00000915136.1		c.624C>G	p.Thr208Thr	synonymous	Exon 8 of 10	ENSP00000585195.1

Frequencies

GnomAD3 genomes AF: 0.00391 AC: 594 AN: 152110 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.000942

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00550

Gnomad ASJ AF: 0.0320

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0106

Gnomad FIN AF: 0.000472

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.00419

Gnomad OTH AF: 0.00764

GnomAD2 exomes AF: 0.00515 AC: 1295 AN: 251406 AF XY: 0.00582

Gnomad AFR exome AF: 0.000431

Gnomad AMR exome AF: 0.00373

Gnomad ASJ exome AF: 0.0313

Gnomad EAS exome AF: 0.000163

Gnomad FIN exome AF: 0.000462

Gnomad NFE exome AF: 0.00450

Gnomad OTH exome AF: 0.00684

GnomAD4 exome AF: 0.00452 AC: 6612 AN: 1461864 Hom.: 43 Cov.: 31 AF XY: 0.00480 AC XY: 3488 AN XY: 727232

African (AFR) AF: 0.000777 AC: 26 AN: 33480

American (AMR) AF: 0.00391 AC: 175 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0311 AC: 814 AN: 26134

East Asian (EAS) AF: 0.0000756 AC: 3 AN: 39694

South Asian (SAS) AF: 0.00940 AC: 811 AN: 86256

European-Finnish (FIN) AF: 0.000562 AC: 30 AN: 53420

Middle Eastern (MID) AF: 0.0128 AC: 74 AN: 5768

European-Non Finnish (NFE) AF: 0.00383 AC: 4260 AN: 1111996

Other (OTH) AF: 0.00694 AC: 419 AN: 60392

GnomAD4 genome AF: 0.00390 AC: 593 AN: 152228 Hom.: 2 Cov.: 32 AF XY: 0.00394 AC XY: 293 AN XY: 74424

African (AFR) AF: 0.000939 AC: 39 AN: 41538

American (AMR) AF: 0.00549 AC: 84 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.0320 AC: 111 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.0108 AC: 52 AN: 4810

European-Finnish (FIN) AF: 0.000472 AC: 5 AN: 10604

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.00419 AC: 285 AN: 67998

Other (OTH) AF: 0.00756 AC: 16 AN: 2116

Alfa AF: 0.00668 Hom.: 3

Bravo AF: 0.00417

Asia WGS AF: 0.00549 AC: 19 AN: 3478

EpiCase AF: 0.00622

EpiControl AF: 0.00616

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.40
CADD	Benign	10
DANN	Benign	0.69
PhyloP100		0.80
PromoterAI		0.012	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=92/8	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs56020464; hg19: chr2-208440072;