7-28570494-A-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_182898.4(CREB5):c.421A>T(p.Ser141Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: CREB5 NM_182898.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 8.56

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

Verdict is Uncertain_significance. Variant got 2 ACMG points.

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CREB5	NM_182898.4	c.421A>T	p.Ser141Cys	missense_variant	5/11	ENST00000357727.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CREB5	ENST00000357727.7	c.421A>T	p.Ser141Cys	missense_variant	5/11	1	NM_182898.4	A1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

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

Jan 23, 2024

The c.421A>T (p.S141C) alteration is located in exon 5 (coding exon 5) of the CREB5 gene. This alteration results from a A to T substitution at nucleotide position 421, causing the serine (S) at amino acid position 141 to be replaced by a cysteine (C). 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	0.26
BayesDel_addAF	Uncertain	0.072	D
BayesDel_noAF	Benign	-0.13
Cadd	Uncertain	25
Dann	Benign	0.96
Eigen	Pathogenic	0.79
Eigen_PC	Pathogenic	0.77
FATHMM_MKL	Uncertain	0.88	D
M_CAP	Benign	0.073	D
MetaRNN	Uncertain	0.43	T;T;T;T
MetaSVM	Uncertain	-0.042	T
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Pathogenic	0.80	T
PROVEAN	Benign	-2.0	N;N;N;N
REVEL	Benign	0.26
Sift	Uncertain	0.0010	D;D;D;D
Sift4G	Benign	0.10	T;T;T;T
Polyphen		1.0	.;D;.;.
Vest4		0.57
MutPred		0.24		.;Loss of glycosylation at S141 (P = 0.0226);.;.;
MVP		0.45
MPC		1.1
ClinPred		0.97	D
GERP RS		5.5
Varity_R		0.33
gMVP		0.78

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr7-28610112;