chr5-177457676-C-G

Variant names:

• chr5-177457676-C-G
• rs181426392
• NM_001363541.2:c.1996G>C

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001363541.2(DBN1):​c.1996G>C​(p.Val666Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000561 in 1,605,292 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000026 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: DBN1 NM_001363541.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.87
• Publications: 0 publications found

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

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.12990323).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001363541.2. 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
	DBN1	NM_001363541.2	MANE Select	c.1996G>C	p.Val666Leu	missense	Exon 14 of 15	NP_001350470.2	Q16643-3
	DBN1	NM_001393630.1		c.2002G>C	p.Val668Leu	missense	Exon 15 of 16	NP_001380559.1
	DBN1	NM_001364151.2		c.1993G>C	p.Val665Leu	missense	Exon 14 of 15	NP_001351080.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DBN1	ENST00000393565.6	TSL:5 MANE Select	c.1996G>C	p.Val666Leu	missense	Exon 14 of 15	ENSP00000377195.1	Q16643-3
	DBN1	ENST00000292385.9	TSL:1	c.1864G>C	p.Val622Leu	missense	Exon 14 of 15	ENSP00000292385.5	Q16643-2
	DBN1	ENST00000309007.9	TSL:1	c.1858G>C	p.Val620Leu	missense	Exon 13 of 14	ENSP00000308532.5	Q16643-1

Frequencies

GnomAD3 genomes AF: 0.0000263 AC: 4 AN: 152208 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000799 AC: 2 AN: 250314 AF XY: 0.0000148

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000290

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000883

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000344 AC: 5 AN: 1452966 Hom.: 0 Cov.: 29 AF XY: 0.00000277 AC XY: 2 AN XY: 721658

African (AFR) AF: 0.00 AC: 0 AN: 33312

American (AMR) AF: 0.0000224 AC: 1 AN: 44552

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25980

East Asian (EAS) AF: 0.00 AC: 0 AN: 39486

South Asian (SAS) AF: 0.00 AC: 0 AN: 85926

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53350

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5738

European-Non Finnish (NFE) AF: 0.00000362 AC: 4 AN: 1104698

Other (OTH) AF: 0.00 AC: 0 AN: 59924

GnomAD4 genome AF: 0.0000263 AC: 4 AN: 152326 Hom.: 0 Cov.: 32 AF XY: 0.0000268 AC XY: 2 AN XY: 74496

African (AFR) AF: 0.00 AC: 0 AN: 41560

American (AMR) AF: 0.000196 AC: 3 AN: 15312

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

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

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68032

Other (OTH) AF: 0.00 AC: 0 AN: 2114

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000793

ExAC AF: 0.00000824 AC: 1

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	Benign	0.17
BayesDel_addAF	Benign	-0.0082	T
BayesDel_noAF	Benign	-0.17
CADD	Benign	20
DANN	Uncertain	0.98
DEOGEN2	Benign	0.17	T
Eigen	Benign	-0.25
Eigen_PC	Benign	-0.090
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Uncertain	0.89	D
M_CAP	Uncertain	0.20	D
MetaRNN	Benign	0.13	T
MetaSVM	Uncertain	0.025	D
MutationAssessor	Benign	0.46	N
PhyloP100		1.9
PrimateAI	Uncertain	0.63	T
PROVEAN	Benign	-0.90	N
REVEL	Uncertain	0.32
Sift	Benign	0.094	T
Sift4G	Benign	0.14	T
Polyphen		0.021	B
Vest4		0.30
MutPred		0.10		Gain of glycosylation at P618 (P = 0.0885)
MVP		0.70
MPC		0.13
ClinPred		0.12	T
GERP RS		3.6
Varity_R		0.084
gMVP		0.16
Mutation Taster		=92/8	polymorphism

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

dbSNP: rs181426392; hg19: chr5-176884677;