Variant chr1-114595834-C-G details in Genebe, Genetics Data Aggregator

Variant summary

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

The NM_001256404.2(DENND2C):c.2323G>C(p.Glu775Gln) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.00000137 in 1,461,438 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/23 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

DENND2C
NM_001256404.2 missense, splice_region

Scores

Splicing: ADA: 0.001314

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.69

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:

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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=0.07315612).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DENND2C	NM_001256404.2 linkuse as main transcript	c.2323G>C	p.Glu775Gln	missense_variant, splice_region_variant	17/21	ENST00000393274.6	NP_001243333.1	Q68D51-1
DENND2C	NM_198459.4 linkuse as main transcript	c.2152G>C	p.Glu718Gln	missense_variant, splice_region_variant	14/18		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.2323G>C	p.Glu775Gln	missense_variant, splice_region_variant	17/21	5	NM_001256404.2	ENSP00000376955.1	Q68D51-1
DENND2C	ENST00000481894.1 linkuse as main transcript	n.1611G>C		splice_region_variant, non_coding_transcript_exon_variant	14/18	1
DENND2C	ENST00000393276.7 linkuse as main transcript	c.2152G>C	p.Glu718Gln	missense_variant, splice_region_variant	14/18	5		ENSP00000376957.3	Q68D51-3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000137

AC:

AN:

1461438

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727062

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

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

Cov.:

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

Jan 24, 2023

The c.2152G>C (p.E718Q) alteration is located in exon 14 (coding exon 13) of the DENND2C gene. This alteration results from a G to C substitution at nucleotide position 2152, causing the glutamic acid (E) at amino acid position 718 to be replaced by a glutamine (Q). 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

0.11

BayesDel_addAF

Benign

-0.31

BayesDel_noAF

Benign

-0.68

CADD

Benign

DANN

Benign

0.17

DEOGEN2

Benign

0.0025

.;T;T

Eigen

Benign

-0.26

Eigen_PC

Benign

-0.00046

FATHMM_MKL

Uncertain

0.80

LIST_S2

Benign

0.69

T;.;T

M_CAP

Benign

0.0055

MetaRNN

Benign

0.073

T;T;T

MetaSVM

Benign

-0.95

MutationAssessor

Benign

0.070

.;N;N

PrimateAI

Uncertain

0.60

PROVEAN

Benign

1.8

N;N;.

REVEL

Benign

0.11

Sift

Benign

1.0

T;T;.

Sift4G

Benign

1.0

T;T;T

Polyphen

0.0020

B;B;B

Vest4

0.18

MutPred

0.33

.;Gain of helix (P = 0.062);Gain of helix (P = 0.062);

MVP

0.31

MPC

0.073

ClinPred

0.80

GERP RS

5.9

Varity_R

0.18

gMVP

0.33

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.0013

dbscSNV1_RF

Benign

0.042

SpliceAI score (max)

0.030

Details are displayed if max score is > 0.2

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

Publications

No publications associated with this variant yet.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over