Variant 7-140546882-T-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4

The NM_015689.5(DENND2A):c.2095A>T(p.Met699Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000565 in 1,614,060 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00035 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00059 ( 0 hom. )

Consequence

DENND2A
NM_015689.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.85

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 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.3118497).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DENND2A	NM_015689.5 linkuse as main transcript	c.2095A>T	p.Met699Leu	missense_variant	13/20	ENST00000496613.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DENND2A	ENST00000496613.6 linkuse as main transcript	c.2095A>T	p.Met699Leu	missense_variant	13/20	2	NM_015689.5	P1	Q9ULE3-1

Frequencies

GnomAD3 genomes

AF:

0.000348

AC:

AN:

152208

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000145

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

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:

0.000676

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000365

AC:

AN:

249554

Hom.:

AF XY:

0.000421

AC XY:

AN XY:

135394

show subpopulations

Gnomad AFR exome

AF:

0.000129

Gnomad AMR exome

AF:

0.0000290

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:

0.000768

Gnomad OTH exome

AF:

0.000165

GnomAD4 exome

AF:

0.000588

AC:

859

AN:

1461852

Hom.:

Cov.:

AF XY:

0.000620

AC XY:

451

AN XY:

727226

show subpopulations

Gnomad4 AFR exome

AF:

0.000149

Gnomad4 AMR exome

AF:

0.0000671

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.0000374

Gnomad4 NFE exome

AF:

0.000732

Gnomad4 OTH exome

AF:

0.000580

GnomAD4 genome

AF:

0.000348

AC:

AN:

152208

Hom.:

Cov.:

AF XY:

0.000350

AC XY:

AN XY:

74368

show subpopulations

Gnomad4 AFR

AF:

0.000145

Gnomad4 AMR

AF:

0.0000655

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000676

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000536

Hom.:

Bravo

AF:

0.000332

TwinsUK

AF:

0.00135

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.00120

AC:

ExAC

AF:

0.000331

AC:

EpiCase

AF:

0.000491

EpiControl

AF:

0.000889

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

Feb 02, 2022

The c.2095A>T (p.M699L) alteration is located in exon 11 (coding exon 11) of the DENND2A gene. This alteration results from a A to T substitution at nucleotide position 2095, causing the methionine (M) at amino acid position 699 to be replaced by a leucine (L). 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

0.52

BayesDel_addAF

Benign

-0.22

BayesDel_noAF

Benign

-0.12

Cadd

Pathogenic

Dann

Uncertain

0.99

DEOGEN2

Benign

0.13

T;T;T;.;.

Eigen

Uncertain

0.52

Eigen_PC

Uncertain

0.58

FATHMM_MKL

Pathogenic

0.99

M_CAP

Benign

0.0091

MetaRNN

Benign

0.31

T;T;T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.40

N;N;N;.;N

MutationTaster

Benign

1.0

D;D;D;D

PrimateAI

Pathogenic

0.81

PROVEAN

Uncertain

-2.8

D;D;D;D;D

REVEL

Uncertain

0.32

Sift

Pathogenic

0.0

D;D;D;T;D

Sift4G

Pathogenic

0.0

D;D;D;.;D

Polyphen

0.74

P;P;P;.;D

Vest4

0.61

MutPred

0.64

Loss of catalytic residue at V695 (P = 0.0223);Loss of catalytic residue at V695 (P = 0.0223);Loss of catalytic residue at V695 (P = 0.0223);.;Loss of catalytic residue at V695 (P = 0.0223);

MVP

0.59

MPC

0.71

ClinPred

0.32

GERP RS

5.6

Varity_R

0.87

gMVP

0.66

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