19-6468054-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_024898.4(DENND1C):ā€‹c.1856C>Gā€‹(p.Ser619Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000434 in 1,613,782 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (ā˜…).

Frequency

Genomes: š‘“ 0.0000066 ( 0 hom., cov: 31)
Exomes š‘“: 0.0000041 ( 0 hom. )

Consequence

DENND1C
NM_024898.4 missense

Scores

3
16

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.86
Variant links:
Genes affected
DENND1C (HGNC:26225): (DENN domain containing 1C) The protein encoded by this gene functions as a guanine nucleotide exchange factor for the early endosomal small GTPase RAB35, which regulates endosomal membrane trafficking and is involved in actin polymerization. The encoded protein activates RAB35 by promoting the exchange of RAB35-bound GDP for GTP. This gene may play a role in linking RAB35 activation with the clathrin machinery. [provided by RefSeq, May 2017]

Genome browser will be placed here

ACMG classification

Classification made for transcript

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=0.1650761).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
DENND1CNM_024898.4 linkuse as main transcriptc.1856C>G p.Ser619Cys missense_variant 23/23 ENST00000381480.7 NP_079174.2 Q8IV53-1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
DENND1CENST00000381480.7 linkuse as main transcriptc.1856C>G p.Ser619Cys missense_variant 23/231 NM_024898.4 ENSP00000370889.1 Q8IV53-1

Frequencies

GnomAD3 genomes
AF:
0.00000657
AC:
1
AN:
152146
Hom.:
0
Cov.:
31
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.0000654
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:
0.00
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000120
AC:
3
AN:
248962
Hom.:
0
AF XY:
0.0000148
AC XY:
2
AN XY:
135076
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.0000870
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000410
AC:
6
AN:
1461636
Hom.:
0
Cov.:
32
AF XY:
0.00000550
AC XY:
4
AN XY:
727102
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.0000895
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000180
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.00000657
AC:
1
AN:
152146
Hom.:
0
Cov.:
31
AF XY:
0.00
AC XY:
0
AN XY:
74316
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.0000654
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.00000756
ExAC
AF:
0.00000827
AC:
1

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsDec 03, 2021The c.1856C>G (p.S619C) alteration is located in exon 23 (coding exon 23) of the DENND1C gene. This alteration results from a C to G substitution at nucleotide position 1856, causing the serine (S) at amino acid position 619 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
0.077
BayesDel_addAF
Benign
-0.43
T
BayesDel_noAF
Benign
-0.65
CADD
Benign
21
DANN
Uncertain
0.98
DEOGEN2
Benign
0.0066
T;.
Eigen
Benign
-0.27
Eigen_PC
Benign
-0.35
FATHMM_MKL
Benign
0.36
N
LIST_S2
Benign
0.52
T;T
M_CAP
Benign
0.0040
T
MetaRNN
Benign
0.17
T;T
MetaSVM
Benign
-0.97
T
MutationAssessor
Benign
0.90
L;.
PrimateAI
Benign
0.28
T
PROVEAN
Benign
-1.6
N;N
REVEL
Benign
0.099
Sift
Uncertain
0.0080
D;D
Sift4G
Uncertain
0.051
T;T
Polyphen
0.97
D;.
Vest4
0.19
MutPred
0.23
Loss of phosphorylation at S619 (P = 0.0138);.;
MVP
0.23
MPC
0.040
ClinPred
0.20
T
GERP RS
4.3
Varity_R
0.11
gMVP
0.18

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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs755553002; hg19: chr19-6468065; API