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GeneBe

1-111188729-G-A

Variant summary

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

The NM_024901.5(DENND2D):c.1072C>T(p.Leu358Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000162 in 1,614,092 control chromosomes in the GnomAD database, including 1 homozygotes. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00013 ( 0 hom., cov: 31)
Exomes 𝑓: 0.00017 ( 1 hom. )

Consequence

DENND2D
NM_024901.5 missense

Scores

9
10

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.52
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]

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/exons MANE UniProt
DENND2DNM_024901.5 linkuse as main transcriptc.1072C>T p.Leu358Phe missense_variant 10/12 ENST00000357640.9

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
DENND2DENST00000357640.9 linkuse as main transcriptc.1072C>T p.Leu358Phe missense_variant 10/121 NM_024901.5 P4Q9H6A0-1
DENND2DENST00000369752.5 linkuse as main transcriptc.1063C>T p.Leu355Phe missense_variant 10/122 A1Q9H6A0-2
DENND2DENST00000468692.1 linkuse as main transcriptn.175C>T non_coding_transcript_exon_variant 2/42

Frequencies

GnomAD3 genomes
AF:
0.000131
AC:
20
AN:
152144
Hom.:
0
Cov.:
31
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:
0.000943
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.000132
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.000135
AC:
34
AN:
251480
Hom.:
0
AF XY:
0.000110
AC XY:
15
AN XY:
135912
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:
0.00102
Gnomad NFE exome
AF:
0.000105
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.000166
AC:
242
AN:
1461830
Hom.:
1
Cov.:
31
AF XY:
0.000157
AC XY:
114
AN XY:
727218
show subpopulations
Gnomad4 AFR exome
AF:
0.0000299
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.000899
Gnomad4 NFE exome
AF:
0.000170
Gnomad4 OTH exome
AF:
0.0000662
GnomAD4 genome
AF:
0.000131
AC:
20
AN:
152262
Hom.:
0
Cov.:
31
AF XY:
0.000175
AC XY:
13
AN XY:
74446
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:
0.000943
Gnomad4 NFE
AF:
0.000132
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.000153
Hom.:
0
Bravo
AF:
0.0000718
ESP6500AA
AF:
0.00
AC:
0
ESP6500EA
AF:
0.000116
AC:
1
ExAC
AF:
0.0000988
AC:
12
EpiCase
AF:
0.000164
EpiControl
AF:
0.0000593

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 submitterclinical testingAmbry GeneticsFeb 01, 2023The c.1072C>T (p.L358F) alteration is located in exon 10 (coding exon 10) of the DENND2D gene. This alteration results from a C to T substitution at nucleotide position 1072, causing the leucine (L) at amino acid position 358 to be replaced by a phenylalanine (F). 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
0.16
BayesDel_addAF
Benign
-0.22
T
BayesDel_noAF
Benign
-0.31
Cadd
Uncertain
25
Dann
Uncertain
1.0
DEOGEN2
Benign
0.21
T;.
Eigen
Uncertain
0.57
Eigen_PC
Uncertain
0.49
FATHMM_MKL
Uncertain
0.85
D
LIST_S2
Benign
0.84
T;T
M_CAP
Benign
0.031
D
MetaRNN
Uncertain
0.43
T;T
MetaSVM
Benign
-1.1
T
MutationAssessor
Uncertain
2.7
M;.
MutationTaster
Benign
0.98
D;D
PrimateAI
Benign
0.42
T
PROVEAN
Uncertain
-2.5
D;D
REVEL
Uncertain
0.34
Sift
Uncertain
0.0080
D;D
Sift4G
Benign
0.18
T;T
Polyphen
1.0
D;D
Vest4
0.65
MVP
0.64
MPC
1.1
ClinPred
0.35
T
GERP RS
5.2
Varity_R
0.40
gMVP
0.68

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.

Other links and lift over

dbSNP: rs201051055; hg19: chr1-111731351; API