Genetic Variant DENND1C:n.*41A>G (chr19-6475602-T-C) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The ENST00000590867.5(DENND1C):n.*41A>G variant causes a non coding transcript exon change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.621 in 1,613,568 control chromosomes in the GnomAD database, including 318,251 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.56 ( 24227 hom., cov: 33)

Exomes 𝑓: 0.63 ( 294024 hom. )

Consequence

DENND1C
ENST00000590867.5 non_coding_transcript_exon

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -1.57

Publications

20 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:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.82).

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.642 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DENND1C	NM_024898.4 link	c.826-17A>G		intron_variant	Intron 12 of 22	ENST00000381480.7	NP_079174.2	Q8IV53-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DENND1C	ENST00000381480.7 link	c.826-17A>G		intron_variant	Intron 12 of 22	1	NM_024898.4	ENSP00000370889.1		Q8IV53-1

Frequencies

GnomAD3 genomes

AF:

0.555

AC:

84332

AN:

151908

Hom.:

24217

Cov.:

show subpopulations

Gnomad AFR

AF:

0.445

Gnomad AMI

AF:

0.800

Gnomad AMR

AF:

0.525

Gnomad ASJ

AF:

0.613

Gnomad EAS

AF:

0.325

Gnomad SAS

AF:

0.520

Gnomad FIN

AF:

0.533

Gnomad MID

AF:

0.456

Gnomad NFE

AF:

0.647

Gnomad OTH

AF:

0.530

GnomAD2 exomes

AF:

0.561

AC:

139607

AN:

248876

AF XY:

0.566

show subpopulations

Gnomad AFR exome

AF:

0.435

Gnomad AMR exome

AF:

0.480

Gnomad ASJ exome

AF:

0.621

Gnomad EAS exome

AF:

0.337

Gnomad FIN exome

AF:

0.540

Gnomad NFE exome

AF:

0.643

Gnomad OTH exome

AF:

0.579

GnomAD4 exome

AF:

0.628

AC:

918084

AN:

1461542

Hom.:

294024

Cov.:

AF XY:

0.625

AC XY:

454199

AN XY:

727054

show subpopulations

African (AFR)

AF:

0.434

AC:

14542

AN:

33478

American (AMR)

AF:

0.489

AC:

21884

AN:

44710

Ashkenazi Jewish (ASJ)

AF:

0.615

AC:

16082

AN:

26130

East Asian (EAS)

AF:

0.309

AC:

12280

AN:

39698

South Asian (SAS)

AF:

0.536

AC:

46246

AN:

86256

European-Finnish (FIN)

AF:

0.549

AC:

29290

AN:

53344

Middle Eastern (MID)

AF:

0.531

AC:

3061

AN:

5766

European-Non Finnish (NFE)

AF:

0.664

AC:

738527

AN:

1111790

Other (OTH)

AF:

0.599

AC:

36172

AN:

60370

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

22340

44681

67021

89362

111702

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

19084

38168

57252

76336

95420

<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:

0.555

AC:

84385

AN:

152026

Hom.:

24227

Cov.:

AF XY:

0.548

AC XY:

40735

AN XY:

74324

show subpopulations

African (AFR)

AF:

0.445

AC:

18431

AN:

41426

American (AMR)

AF:

0.525

AC:

8025

AN:

15296

Ashkenazi Jewish (ASJ)

AF:

0.613

AC:

2124

AN:

3466

East Asian (EAS)

AF:

0.325

AC:

1682

AN:

5170

South Asian (SAS)

AF:

0.521

AC:

2514

AN:

4828

European-Finnish (FIN)

AF:

0.533

AC:

5638

AN:

10574

Middle Eastern (MID)

AF:

0.452

AC:

133

AN:

294

European-Non Finnish (NFE)

AF:

0.647

AC:

43991

AN:

67956

Other (OTH)

AF:

0.532

AC:

1122

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.510

Heterozygous variant carriers

1962

3923

5885

7846

9808

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

718

1436

2154

2872

3590

<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:

0.608

Hom.:

91595

Bravo

AF:

0.553

Asia WGS

AF:

0.423

AC:

1470

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.82

CADD

Benign

0.087

(source)

DANN

Benign

0.35

PhyloP100

-1.6

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.050

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over