Genetic Variant DENND2C:p.Ile794Asn (chr1-114594523-A-T) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

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

The NM_001256404.2(DENND2C):c.2381T>A(p.Ile794Asn) variant causes a missense change. The variant allele was found at a frequency of 0.000018 in 1,613,868 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000033 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000016 ( 0 hom. )

Consequence

DENND2C
NM_001256404.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.78

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:

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 rank	MANE	Protein	UniProt
DENND2C	NM_001256404.2 link	c.2381T>A	p.Ile794Asn	missense_variant	Exon 18 of 21	ENST00000393274.6	NP_001243333.1	Q68D51-1
DENND2C	NM_198459.4 link	c.2210T>A	p.Ile737Asn	missense_variant	Exon 15 of 18		NP_940861.3	Q68D51-3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
DENND2C	ENST00000393274.6 link	c.2381T>A	p.Ile794Asn	missense_variant	Exon 18 of 21	5	NM_001256404.2	ENSP00000376955.1	Q68D51-1
DENND2C	ENST00000481894.1 link	n.1965T>A		non_coding_transcript_exon_variant	Exon 16 of 18	1
DENND2C	ENST00000393276.7 link	c.2210T>A	p.Ile737Asn	missense_variant	Exon 15 of 18	5		ENSP00000376957.3	Q68D51-3

Frequencies

GnomAD3 genomes

AF:

0.0000329

AC:

AN:

152116

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

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:

0.0000588

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000239

AC:

AN:

251368

Hom.:

AF XY:

0.0000221

AC XY:

AN XY:

135864

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000528

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000164

AC:

AN:

1461752

Hom.:

Cov.:

AF XY:

0.0000206

AC XY:

AN XY:

727182

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:

0.0000375

Gnomad4 NFE exome

AF:

0.0000108

Gnomad4 OTH exome

AF:

0.0000828

GnomAD4 genome

AF:

0.0000329

AC:

AN:

152116

Hom.:

Cov.:

AF XY:

0.0000538

AC XY:

AN XY:

74314

show subpopulations

Gnomad4 AFR

AF:

0.0000241

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:

0.0000588

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000756

ExAC

AF:

0.0000412

AC:

EpiCase

AF:

0.000164

EpiControl

AF:

0.000296

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Apr 19, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.2210T>A (p.I737N) alteration is located in exon 15 (coding exon 14) of the DENND2C gene. This alteration results from a T to A substitution at nucleotide position 2210, causing the isoleucine (I) at amino acid position 737 to be replaced by an asparagine (N). 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

Pathogenic

0.73

BayesDel_addAF

Benign

-0.18

BayesDel_noAF

Benign

-0.34

CADD

Pathogenic

DANN

Uncertain

0.99

DEOGEN2

Benign

0.057

.;T;T

Eigen

Uncertain

0.50

Eigen_PC

Uncertain

0.47

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

0.97

D;.;D

M_CAP

Benign

0.032

MetaRNN

Uncertain

0.70

D;D;D

MetaSVM

Benign

-1.1

MutationAssessor

Uncertain

2.6

.;M;M

PrimateAI

Uncertain

0.74

PROVEAN

Pathogenic

-4.9

D;D;.

REVEL

Benign

0.20

Sift

Uncertain

0.0030

D;D;.

Sift4G

Uncertain

0.018

D;D;D

Polyphen

0.99

D;D;D

Vest4

0.81

MutPred

0.45

.;Gain of disorder (P = 0.0066);Gain of disorder (P = 0.0066);

MVP

0.42

MPC

0.47

ClinPred

0.88

GERP RS

3.6

Varity_R

0.67

gMVP

0.73

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