2-207575348-C-G

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Moderate BP6_Moderate BP7 BS2

The NM_004379.5(CREB1):c.582C>G(p.Thr194=) 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 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 criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.804

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 Benign. Variant got -9 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]. Clinvar id is 769581.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=0.804 with no splicing effect.
• BS2: High AC in GnomAd at 594 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CREB1	NM_004379.5	c.582C>G	p.Thr194=	synonymous_variant	6/8	ENST00000353267.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CREB1	ENST00000353267.8	c.582C>G	p.Thr194=	synonymous_variant	6/8	1	NM_004379.5	P1

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

GnomAD3 exomes AF: 0.00515 AC: 1295 AN: 251406 Hom.: 18 AF XY: 0.00582 AC XY: 791 AN XY: 135866

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 SAS exome AF: 0.00905

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

Gnomad4 AFR exome AF: 0.000777

Gnomad4 AMR exome AF: 0.00391

Gnomad4 ASJ exome AF: 0.0311

Gnomad4 EAS exome AF: 0.0000756

Gnomad4 SAS exome AF: 0.00940

Gnomad4 FIN exome AF: 0.000562

Gnomad4 NFE exome AF: 0.00383

Gnomad4 OTH exome AF: 0.00694

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

Gnomad4 AFR AF: 0.000939

Gnomad4 AMR AF: 0.00549

Gnomad4 ASJ AF: 0.0320

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.0108

Gnomad4 FIN AF: 0.000472

Gnomad4 NFE AF: 0.00419

Gnomad4 OTH AF: 0.00756

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

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Dec 31, 2019

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.40
Cadd	Benign	10
Dann	Benign	0.69
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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

Publications

LitVar

Other links and lift over

dbSNP: rs56020464; hg19: chr2-208440072;