Genetic Variant NM_024898.4:c.2402G>A (chr19-6467508-C-T) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_024898.4(DENND1C):c.2402G>A(p.Gly801Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000315 in 1,588,778 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 31)

Exomes 𝑓: 0.000033 ( 0 hom. )

Consequence

DENND1C
NM_024898.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.501

Publications

0 publications found

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]

DENND1C links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.0643374).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_024898.4. 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
	DENND1C	NM_024898.4	MANE Select	c.2402G>A	p.Gly801Asp	missense	Exon 23 of 23	NP_079174.2	Q8IV53-1
	DENND1C	NM_001290331.2		c.2270G>A	p.Gly757Asp	missense	Exon 21 of 21	NP_001277260.1	Q8IV53-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
DENND1C	ENST00000381480.7	TSL:1 MANE Select	c.2402G>A	p.Gly801Asp	missense	Exon 23 of 23	ENSP00000370889.1	Q8IV53-1
DENND1C	ENST00000590867.5	TSL:1	n.*1634G>A		non_coding_transcript_exon	Exon 21 of 21	ENSP00000465675.1	K7EKL5
DENND1C	ENST00000590867.5	TSL:1	n.*1634G>A		3_prime_UTR	Exon 21 of 21	ENSP00000465675.1	K7EKL5

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152112

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000265

AC:

AN:

226234

AF XY:

0.0000406

show subpopulations

Gnomad AFR exome

AF:

0.0000687

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000478

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000327

AC:

AN:

1436666

Hom.:

Cov.:

AF XY:

0.0000378

AC XY:

AN XY:

714090

show subpopulations

African (AFR)

AF:

0.0000314

AC:

AN:

31846

American (AMR)

AF:

0.00

AC:

AN:

38412

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24898

East Asian (EAS)

AF:

0.00

AC:

AN:

38868

South Asian (SAS)

AF:

0.00

AC:

AN:

82540

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52884

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5584

European-Non Finnish (NFE)

AF:

0.0000408

AC:

AN:

1102474

Other (OTH)

AF:

0.0000169

AC:

AN:

59160

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.491

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000197

AC:

AN:

152112

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74308

show subpopulations

African (AFR)

AF:

0.0000241

AC:

AN:

41434

American (AMR)

AF:

0.00

AC:

AN:

15262

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5188

South Asian (SAS)

AF:

0.00

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10606

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000294

AC:

AN:

68006

Other (OTH)

AF:

0.00

AC:

AN:

2090

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.458

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0000508

Hom.:

Bravo

AF:

0.0000264

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000259

AC:

ExAC

AF:

0.0000331

AC:

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.15

BayesDel_addAF

Benign

-0.31

BayesDel_noAF

Benign

-0.51

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.0041

Eigen

Benign

-0.58

Eigen_PC

Benign

-0.56

FATHMM_MKL

Benign

0.20

LIST_S2

Benign

0.69

M_CAP

Benign

0.010

MetaRNN

Benign

0.064

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.97

PhyloP100

0.50

PrimateAI

Benign

0.41

PROVEAN

Benign

-0.80

REVEL

Benign

0.052

Sift

Benign

0.031

Sift4G

Pathogenic

0.0

Polyphen

0.29

Vest4

0.34

MVP

0.12

MPC

0.12

ClinPred

0.10

GERP RS

4.0

Varity_R

0.052

gMVP

0.070

Mutation Taster

=97/3

polymorphism

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over