Genetic Variant DENND2C:p.Arg663Gln (chr1-114600321-C-T) – ACMG Classification: Uncertain_significance (3 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP3

The NM_001256404.2(DENND2C):c.1988G>A(p.Arg663Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000958 in 1,461,832 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000096 ( 0 hom. )

Consequence

DENND2C
NM_001256404.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.91

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 made for transcript

Verdict is Uncertain_significance. Variant got 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.819

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DENND2C	NM_001256404.2 link	c.1988G>A	p.Arg663Gln	missense_variant	Exon 15 of 21	ENST00000393274.6	NP_001243333.1	Q68D51-1
DENND2C	NM_198459.4 link	c.1817G>A	p.Arg606Gln	missense_variant	Exon 12 of 18		NP_940861.3	Q68D51-3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
DENND2C	ENST00000393274.6 link	c.1988G>A	p.Arg663Gln	missense_variant	Exon 15 of 21	5	NM_001256404.2	ENSP00000376955.1	Q68D51-1
DENND2C	ENST00000481894.1 link	n.1276G>A		non_coding_transcript_exon_variant	Exon 12 of 18	1
DENND2C	ENST00000393276.7 link	c.1817G>A	p.Arg606Gln	missense_variant	Exon 12 of 18	5		ENSP00000376957.3	Q68D51-3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000796

AC:

AN:

251386

Hom.:

AF XY:

0.00000736

AC XY:

AN XY:

135850

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000109

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000958

AC:

AN:

1461832

Hom.:

Cov.:

AF XY:

0.0000110

AC XY:

AN XY:

727210

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000151

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.0000187

Gnomad4 NFE exome

AF:

0.00000360

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

Cov.:

Bravo

AF:

0.00000378

ExAC

AF:

0.0000165

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Jan 18, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1817G>A (p.R606Q) alteration is located in exon 12 (coding exon 11) of the DENND2C gene. This alteration results from a G to A substitution at nucleotide position 1817, causing the arginine (R) at amino acid position 606 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

Uncertain

0.43

BayesDel_addAF

Benign

-0.094

BayesDel_noAF

Benign

-0.15

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.020

.;T;T

Eigen

Pathogenic

0.81

Eigen_PC

Pathogenic

0.80

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

0.98

D;.;D

M_CAP

Benign

0.047

MetaRNN

Pathogenic

0.82

D;D;D

MetaSVM

Benign

-1.1

MutationAssessor

Uncertain

2.1

.;M;M

PrimateAI

Uncertain

0.71

PROVEAN

Uncertain

-3.7

D;D;.

REVEL

Uncertain

0.41

Sift

Uncertain

0.0060

D;D;.

Sift4G

Uncertain

0.015

D;D;D

Polyphen

0.94

P;D;D

Vest4

0.80

MutPred

0.63

.;Loss of phosphorylation at S662 (P = 0.1422);Loss of phosphorylation at S662 (P = 0.1422);

MVP

0.58

MPC

0.40

ClinPred

0.99

GERP RS

5.6

Varity_R

0.45

gMVP

0.64

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.11

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