Variant 7-140521924-C-T 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_015689.5(DENND2A):c.2842G>A(p.Val948Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000124 in 1,614,092 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

DENND2A
NM_015689.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.04

Variant links:

Genes affected

DENND2A (HGNC:22212): (DENN domain containing 2A) Enables guanyl-nucleotide exchange factor activity. Involved in retrograde transport, endosome to Golgi. Located in actin cytoskeleton. [provided by Alliance of Genome Resources, Apr 2022]

DENND2A links:

Genome browser will be placed here

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=0.20638019).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
DENND2A	NM_015689.5 linkuse as main transcript	c.2842G>A	p.Val948Ile	missense_variant	18/20	ENST00000496613.6
DENND2A	NM_001318052.2 linkuse as main transcript	c.2842G>A	p.Val948Ile	missense_variant	17/19
DENND2A	NM_001362678.2 linkuse as main transcript	c.2842G>A	p.Val948Ile	missense_variant	18/20
DENND2A	NR_134477.1 linkuse as main transcript	n.2929G>A		non_coding_transcript_exon_variant	16/18

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DENND2A	ENST00000496613.6 linkuse as main transcript	c.2842G>A	p.Val948Ile	missense_variant	18/20	2	NM_015689.5	P1	Q9ULE3-1
DENND2A	ENST00000275884.10 linkuse as main transcript	c.2842G>A	p.Val948Ile	missense_variant	17/19	1		P1	Q9ULE3-1
DENND2A	ENST00000537639.5 linkuse as main transcript	c.2842G>A	p.Val948Ile	missense_variant	16/18	1		P1	Q9ULE3-1
DENND2A	ENST00000461883.5 linkuse as main transcript	c.*189G>A		3_prime_UTR_variant, NMD_transcript_variant	16/18	1

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152256

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461836

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

727224

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:

0.00

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152256

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74388

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.0000654

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000416

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 30, 2024

The c.2842G>A (p.V948I) alteration is located in exon 16 (coding exon 16) of the DENND2A gene. This alteration results from a G to A substitution at nucleotide position 2842, causing the valine (V) at amino acid position 948 to be replaced by an isoleucine (I). 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

0.099

BayesDel_addAF

Benign

-0.19

BayesDel_noAF

Benign

-0.51

Cadd

Benign

Dann

Uncertain

0.99

DEOGEN2

Benign

0.020

T;T;T

Eigen

Benign

-0.069

Eigen_PC

Benign

0.0051

FATHMM_MKL

Uncertain

0.95

M_CAP

Benign

0.0086

MetaRNN

Benign

0.21

T;T;T

MetaSVM

Benign

-0.99

MutationAssessor

Benign

1.5

L;L;L

MutationTaster

Benign

1.0

D;D;D

PrimateAI

Uncertain

0.56

PROVEAN

Benign

-0.46

N;N;N

REVEL

Benign

0.067

Sift

Benign

0.092

T;T;T

Sift4G

Benign

0.090

T;T;T

Polyphen

0.13

B;B;B

Vest4

0.27

MutPred

0.48

Loss of MoRF binding (P = 0.1183);Loss of MoRF binding (P = 0.1183);Loss of MoRF binding (P = 0.1183);

MVP

0.16

MPC

0.19

ClinPred

0.64

GERP RS

2.8

Varity_R

0.031

gMVP

0.17

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