chr7-28570486-C-T

Variant names:

• chr7-28570486-C-T
• NM_182898.4:c.413C>T

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_182898.4(CREB5):​c.413C>T​(p.Pro138Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,870 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: CREB5 NM_182898.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.25
• Publications: 0 publications found

Genes affected

CREB5 (HGNC:16844): (cAMP responsive element binding protein 5) The product of this gene belongs to the CRE (cAMP response element)-binding protein family. Members of this family contain zinc-finger and bZIP DNA-binding domains. The encoded protein specifically binds to CRE as a homodimer or a heterodimer with c-Jun or CRE-BP1, and functions as a CRE-dependent trans-activator. Alternatively spliced transcript variants encoding different isoforms have been identified. [provided by RefSeq, Jul 2008]

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_182898.4. 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
	CREB5	NM_182898.4	MANE Select	c.413C>T	p.Pro138Leu	missense	Exon 5 of 11	NP_878901.2	Q02930-1
	CREB5	NM_004904.4		c.392C>T	p.Pro131Leu	missense	Exon 5 of 11	NP_004895.2	Q02930-2
	CREB5	NM_182899.5		c.314C>T	p.Pro105Leu	missense	Exon 4 of 10	NP_878902.2	Q02930-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CREB5	ENST00000357727.7	TSL:1 MANE Select	c.413C>T	p.Pro138Leu	missense	Exon 5 of 11	ENSP00000350359.2	Q02930-1
	CREB5	ENST00000396300.6	TSL:1	c.392C>T	p.Pro131Leu	missense	Exon 5 of 11	ENSP00000379594.2	Q02930-2
	CREB5	ENST00000396299.6	TSL:1	c.314C>T	p.Pro105Leu	missense	Exon 4 of 10	ENSP00000379593.2	Q02930-3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461870 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 727236

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86254

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111996

Other (OTH) AF: 0.00 AC: 0 AN: 60394

GnomAD4 genome Cov.: 32

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	Pathogenic	0.67
BayesDel_addAF	Uncertain	0.076	D
BayesDel_noAF	Benign	-0.13
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.71	D
Eigen	Pathogenic	0.78
Eigen_PC	Pathogenic	0.73
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Uncertain	0.11	D
MetaRNN	Uncertain	0.65	D
MetaSVM	Uncertain	0.043	D
MutationAssessor	Uncertain	2.8	M
PhyloP100		7.3
PrimateAI	Pathogenic	0.83	D
PROVEAN	Pathogenic	-5.3	D
REVEL	Uncertain	0.41
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.0020	D
Polyphen		1.0	D
Vest4		0.57
MutPred		0.34		Loss of glycosylation at P138 (P = 0.0372)
MVP		0.53
MPC		0.94
ClinPred		1.0	D
GERP RS		5.5
Varity_R		0.46
gMVP		0.75
Mutation Taster		=38/62	disease causing

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

hg19: chr7-28610104; COSMIC: COSV100745031; COSMIC: COSV100745031;