chr7-140523418-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP3

The NM_015689.5(DENND2A):​c.2554G>A​(p.Asp852Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000805 in 1,613,960 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0000075 ( 0 hom. )

Consequence

DENND2A
NM_015689.5 missense

Scores

5
8
6

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.52
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 3 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.805

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
DENND2ANM_015689.5 linkc.2554G>A p.Asp852Asn missense_variant Exon 17 of 20 ENST00000496613.6 NP_056504.3 Q9ULE3-1A2RUF6
DENND2ANM_001318052.2 linkc.2554G>A p.Asp852Asn missense_variant Exon 16 of 19 NP_001304981.1 Q9ULE3-1
DENND2ANM_001362678.2 linkc.2554G>A p.Asp852Asn missense_variant Exon 17 of 20 NP_001349607.1
DENND2ANR_134477.1 linkn.2641G>A non_coding_transcript_exon_variant Exon 15 of 18

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
DENND2AENST00000496613.6 linkc.2554G>A p.Asp852Asn missense_variant Exon 17 of 20 2 NM_015689.5 ENSP00000419654.1 Q9ULE3-1
DENND2AENST00000275884.10 linkc.2554G>A p.Asp852Asn missense_variant Exon 16 of 19 1 ENSP00000275884.6 Q9ULE3-1
DENND2AENST00000537639.5 linkc.2554G>A p.Asp852Asn missense_variant Exon 15 of 18 1 ENSP00000442245.1 Q9ULE3-1
DENND2AENST00000461883.5 linkn.2496G>A non_coding_transcript_exon_variant Exon 15 of 18 1 ENSP00000417673.1 F8WAT8

Frequencies

GnomAD3 genomes
AF:
0.0000131
AC:
2
AN:
152172
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0000483
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:
0.00
Gnomad OTH
AF:
0.00
GnomAD4 exome
AF:
0.00000753
AC:
11
AN:
1461788
Hom.:
0
Cov.:
30
AF XY:
0.00000138
AC XY:
1
AN XY:
727192
show subpopulations
Gnomad4 AFR exome
AF:
0.0000299
Gnomad4 AMR exome
AF:
0.0000224
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:
0.00000809
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.0000131
AC:
2
AN:
152172
Hom.:
0
Cov.:
32
AF XY:
0.00
AC XY:
0
AN XY:
74336
show subpopulations
Gnomad4 AFR
AF:
0.0000483
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:
0.00
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000283
Hom.:
0
Bravo
AF:
0.0000113
TwinsUK
AF:
0.00
AC:
0
ALSPAC
AF:
0.000259
AC:
1

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Jan 17, 2025
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.2554G>A (p.D852N) alteration is located in exon 15 (coding exon 15) of the DENND2A gene. This alteration results from a G to A substitution at nucleotide position 2554, causing the aspartic acid (D) at amino acid position 852 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
Uncertain
0.54
BayesDel_addAF
Benign
-0.12
T
BayesDel_noAF
Benign
-0.42
CADD
Uncertain
26
DANN
Uncertain
1.0
DEOGEN2
Benign
0.29
T;T;T
Eigen
Uncertain
0.61
Eigen_PC
Uncertain
0.53
FATHMM_MKL
Pathogenic
1.0
D
LIST_S2
Pathogenic
0.99
.;D;.
M_CAP
Benign
0.064
D
MetaRNN
Pathogenic
0.80
D;D;D
MetaSVM
Benign
-1.2
T
MutationAssessor
Pathogenic
3.4
M;M;M
PrimateAI
Uncertain
0.65
T
PROVEAN
Pathogenic
-4.8
D;D;D
REVEL
Uncertain
0.29
Sift
Uncertain
0.0010
D;D;D
Sift4G
Uncertain
0.0030
D;D;D
Polyphen
1.0
D;D;D
Vest4
0.80
MutPred
0.32
Loss of loop (P = 0.1242);Loss of loop (P = 0.1242);Loss of loop (P = 0.1242);
MVP
0.51
MPC
0.74
ClinPred
1.0
D
GERP RS
5.5
Varity_R
0.70
gMVP
0.61

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: rs745399243; hg19: chr7-140223218; COSMIC: COSV52059516; COSMIC: COSV52059516; API