5-177458587-C-T

Variant names:

• chr5-177458587-C-T
• rs1756749566
• NM_001363541.2:c.1385G>A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001363541.2(DBN1):​c.1385G>A​(p.Ser462Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: DBN1 NM_001363541.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.99

Genes affected

DBN1 (HGNC:2695): (drebrin 1) The protein encoded by this gene is a cytoplasmic actin-binding protein thought to play a role in the process of neuronal growth. It is a member of the drebrin family of proteins that are developmentally regulated in the brain. A decrease in the amount of this protein in the brain has been implicated as a possible contributing factor in the pathogenesis of memory disturbance in Alzheimer's disease. At least two alternative splice variants encoding different protein isoforms have been described for this gene. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.116832614).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DBN1	NM_001363541.2	c.1385G>A	p.Ser462Asn	missense_variant	Exon 13 of 15	ENST00000393565.6	NP_001350470.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DBN1	ENST00000393565.6	c.1385G>A	p.Ser462Asn	missense_variant	Exon 13 of 15	5	NM_001363541.2	ENSP00000377195.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 36

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jan 27, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1253G>A (p.S418N) alteration is located in exon 13 (coding exon 12) of the DBN1 gene. This alteration results from a G to A substitution at nucleotide position 1253, causing the serine (S) at amino acid position 418 to be replaced by an asparagine (N). 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	0.084
BayesDel_addAF	Benign	-0.25	T
BayesDel_noAF	Benign	-0.60
CADD	Benign	18
DANN	Benign	0.78
DEOGEN2	Benign	0.11	T;.;.;T
Eigen	Benign	-0.41
Eigen_PC	Benign	-0.36
FATHMM_MKL	Benign	0.40	N
LIST_S2	Benign	0.79	T;T;T;T
M_CAP	Benign	0.016	T
MetaRNN	Benign	0.12	T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.90	L;.;.;.
PrimateAI	Benign	0.45	T
PROVEAN	Benign	-0.50	N;N;N;N
REVEL	Benign	0.095
Sift	Benign	0.30	T;T;D;T
Sift4G	Benign	0.23	T;T;T;T
Polyphen		0.12	B;B;.;.
Vest4		0.16
MutPred		0.20		Loss of glycosylation at S416 (P = 0.009);.;.;.;
MVP		0.40
MPC		0.12
ClinPred		0.16	T
GERP RS		4.2
Varity_R		0.12
gMVP		0.092

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

LitVar

Other links and lift over

dbSNP: rs1756749566; hg19: chr5-176885588;