Genetic Variant DENND2C:p.Glu775Gln (chr1-114595834-C-G) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 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. 17/24 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

Publications

0 publications found

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:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.07315612).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001256404.2. 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
	DENND2C	NM_001256404.2	MANE Select	c.2323G>C	p.Glu775Gln	missense splice_region	Exon 17 of 21	NP_001243333.1	Q68D51-1
	DENND2C	NM_198459.4		c.2152G>C	p.Glu718Gln	missense splice_region	Exon 14 of 18	NP_940861.3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
DENND2C	ENST00000393274.6	TSL:5 MANE Select	c.2323G>C	p.Glu775Gln	missense splice_region	Exon 17 of 21	ENSP00000376955.1	Q68D51-1
DENND2C	ENST00000481894.1	TSL:1	n.1611G>C		splice_region non_coding_transcript_exon	Exon 14 of 18
DENND2C	ENST00000935533.1		c.2323G>C	p.Glu775Gln	missense splice_region	Exon 16 of 20	ENSP00000605592.1

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

African (AFR)

AF:

0.00

AC:

AN:

33470

American (AMR)

AF:

0.00

AC:

AN:

44716

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26112

East Asian (EAS)

AF:

0.00

AC:

AN:

39674

South Asian (SAS)

AF:

0.00

AC:

AN:

86244

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53384

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00000180

AC:

AN:

1111704

Other (OTH)

AF:

0.00

AC:

AN:

60366

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

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

0.11

BayesDel_addAF

Benign

-0.31

BayesDel_noAF

Benign

-0.68

CADD

Benign

(source)

DANN

Benign

0.17

DEOGEN2

Benign

0.0025

Eigen

Benign

-0.26

Eigen_PC

Benign

-0.00046

FATHMM_MKL

Uncertain

0.80

LIST_S2

Benign

0.69

M_CAP

Benign

0.0055

MetaRNN

Benign

0.073

MetaSVM

Benign

-0.95

MutationAssessor

Benign

0.070

PhyloP100

3.7

PrimateAI

Uncertain

0.60

PROVEAN

Benign

1.8

REVEL

Benign

0.11

Sift

Benign

1.0

Sift4G

Benign

1.0

Polyphen

0.0020

Vest4

0.18

MutPred

0.33

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

Mutation Taster

=81/19

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over