Variant 1-114600863-C-T details in Genebe, Genetics Data Aggregator

Variant summary

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

The NM_001256404.2(DENND2C):c.1913G>A(p.Arg638His) variant causes a missense change. The variant allele was found at a frequency of 0.00000744 in 1,613,816 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000062 ( 0 hom. )

Consequence

DENND2C
NM_001256404.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 6.15

Variant links:

Genes affected

DENND2C (HGNC:24748): (DENN domain containing 2C) Enables guanyl-nucleotide exchange factor activity. Predicted to be involved in regulation of catalytic activity. Located in nucleoplasm. [provided by Alliance of Genome Resources, Apr 2022]

DENND2C links:

DENND2C (HGNC:):

DENND2C links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DENND2C	NM_001256404.2 linkuse as main transcript	c.1913G>A	p.Arg638His	missense_variant	14/21	ENST00000393274.6	NP_001243333.1	Q68D51-1
DENND2C	NM_198459.4 linkuse as main transcript	c.1742G>A	p.Arg581His	missense_variant	11/18		NP_940861.3	Q68D51-3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
DENND2C	ENST00000393274.6 linkuse as main transcript	c.1913G>A	p.Arg638His	missense_variant	14/21	5	NM_001256404.2	ENSP00000376955.1	Q68D51-1
DENND2C	ENST00000481894.1 linkuse as main transcript	n.1201G>A		non_coding_transcript_exon_variant	11/18	1
DENND2C	ENST00000393276.7 linkuse as main transcript	c.1742G>A	p.Arg581His	missense_variant	11/18	5		ENSP00000376957.3	Q68D51-3

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152122

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000483

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:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000119

AC:

AN:

251350

Hom.:

AF XY:

0.0000147

AC XY:

AN XY:

135842

show subpopulations

Gnomad AFR exome

AF:

0.0000615

Gnomad AMR exome

AF:

0.00

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:

0.0000176

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000616

AC:

AN:

1461694

Hom.:

Cov.:

AF XY:

0.00000963

AC XY:

AN XY:

727144

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000630

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000197

AC:

AN:

152122

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74298

show subpopulations

Gnomad4 AFR

AF:

0.0000483

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000494

Hom.:

Bravo

AF:

0.0000151

ExAC

AF:

0.0000165

AC:

EpiCase

AF:

0.0000546

EpiControl

AF:

0.00

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 submitter

clinical testing

Ambry Genetics

Sep 26, 2023

The c.1742G>A (p.R581H) alteration is located in exon 11 (coding exon 10) of the DENND2C gene. This alteration results from a G to A substitution at nucleotide position 1742, causing the arginine (R) at amino acid position 581 to be replaced by a histidine (H). 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

0.13

BayesDel_addAF

Benign

-0.16

BayesDel_noAF

Benign

-0.28

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.023

.;T;T

Eigen

Pathogenic

0.76

Eigen_PC

Pathogenic

0.74

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.94

D;.;D

M_CAP

Benign

0.023

MetaRNN

Uncertain

0.64

D;D;D

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.6

.;L;L

PrimateAI

Uncertain

0.72

PROVEAN

Uncertain

-3.6

D;D;D

REVEL

Uncertain

0.32

Sift

Uncertain

0.0040

D;D;D

Sift4G

Uncertain

0.0050

D;D;D

Polyphen

1.0

D;D;D

Vest4

0.65

MVP

0.56

MPC

0.41

ClinPred

0.99

GERP RS

5.3

Varity_R

0.55

gMVP

0.71

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over