Variant chr1-111188277-G-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_024901.5(DENND2D):c.1193C>A(p.Ala398Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000347 in 1,614,186 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00037 ( 1 hom., cov: 32)

Exomes 𝑓: 0.00034 ( 2 hom. )

Consequence

DENND2D
NM_024901.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.180

Variant links:

Genes affected

DENND2D (HGNC:26192): (DENN domain containing 2D) Enables guanyl-nucleotide exchange factor activity. Predicted to be involved in regulation of catalytic activity. Located in cytosol and nucleoplasm. [provided by Alliance of Genome Resources, Apr 2022]

DENND2D links:

DENND2D (HGNC:):

DENND2D links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0027901828).

BS2

High Homozygotes in GnomAdExome4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DENND2D	NM_024901.5 linkuse as main transcript	c.1193C>A	p.Ala398Glu	missense_variant	11/12	ENST00000357640.9	NP_079177.2	Q9H6A0-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
DENND2D	ENST00000357640.9 linkuse as main transcript	c.1193C>A	p.Ala398Glu	missense_variant	11/12	1	NM_024901.5	ENSP00000350266.4	Q9H6A0-1
DENND2D	ENST00000369752.5 linkuse as main transcript	c.1184C>A	p.Ala395Glu	missense_variant	11/12	2		ENSP00000358767.5	Q9H6A0-2
DENND2D	ENST00000468692.1 linkuse as main transcript	n.296C>A		non_coding_transcript_exon_variant	3/4	2

Frequencies

GnomAD3 genomes

AF:

0.000368

AC:

AN:

152178

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

Gnomad ASJ

AF:

0.00922

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000283

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.000235

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.000473

AC:

119

AN:

251474

Hom.:

AF XY:

0.000456

AC XY:

AN XY:

135918

show subpopulations

Gnomad AFR exome

AF:

0.000123

Gnomad AMR exome

AF:

0.000145

Gnomad ASJ exome

AF:

0.00704

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.0000462

Gnomad NFE exome

AF:

0.000299

Gnomad OTH exome

AF:

0.000814

GnomAD4 exome

AF:

0.000345

AC:

504

AN:

1461890

Hom.:

Cov.:

AF XY:

0.000386

AC XY:

281

AN XY:

727246

show subpopulations

Gnomad4 AFR exome

AF:

0.0000896

Gnomad4 AMR exome

AF:

0.000112

Gnomad4 ASJ exome

AF:

0.00815

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.0000374

Gnomad4 NFE exome

AF:

0.000198

Gnomad4 OTH exome

AF:

0.000828

GnomAD4 genome

AF:

0.000368

AC:

AN:

152296

Hom.:

Cov.:

AF XY:

0.000269

AC XY:

AN XY:

74460

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.0000654

Gnomad4 ASJ

AF:

0.00922

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.000283

Gnomad4 NFE

AF:

0.000235

Gnomad4 OTH

AF:

0.000473

Alfa

AF:

0.000714

Hom.:

Bravo

AF:

0.000389

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000581

AC:

ExAC

AF:

0.000461

AC:

EpiCase

AF:

0.000872

EpiControl

AF:

0.000356

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

Jun 06, 2022

The c.1193C>A (p.A398E) alteration is located in exon 11 (coding exon 11) of the DENND2D gene. This alteration results from a C to A substitution at nucleotide position 1193, causing the alanine (A) at amino acid position 398 to be replaced by a glutamic acid (E). 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

0.12

BayesDel_addAF

Benign

-0.35

BayesDel_noAF

Benign

-0.44

CADD

Benign

DANN

Benign

0.82

DEOGEN2

Benign

0.0089

T;.

Eigen

Benign

-0.64

Eigen_PC

Benign

-0.39

FATHMM_MKL

Benign

0.26

LIST_S2

Benign

0.77

T;T

M_CAP

Benign

0.0050

MetaRNN

Benign

0.0028

T;T

MetaSVM

Benign

-0.97

MutationAssessor

Benign

-0.55

N;.

PrimateAI

Benign

0.38

PROVEAN

Benign

2.9

N;N

REVEL

Benign

0.13

Sift

Benign

1.0

T;T

Sift4G

Benign

1.0

T;T

Polyphen

0.13

B;B

Vest4

0.12

MVP

0.40

MPC

0.50

ClinPred

0.022

GERP RS

4.8

Varity_R

0.12

gMVP

0.33

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