1-197553099-C-T
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Variant summary
Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP3_Moderate
The NM_001195215.2(DENND1B):c.1163G>A(p.Arg388Gln) variant causes a missense change. The variant allele was found at a frequency of 0.0000151 in 1,521,824 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: 0.000015 ( 0 hom. )
Consequence
DENND1B
NM_001195215.2 missense
NM_001195215.2 missense
Scores
10
4
1
Clinical Significance
Not reported in ClinVar
Conservation
PhyloP100: 6.15
Genes affected
DENND1B (HGNC:28404): (DENN domain containing 1B) Clathrin (see MIM 118955)-mediated endocytosis is a major mechanism for internalization of proteins and lipids. Members of the connecdenn family, such as DENND1B, function as guanine nucleotide exchange factors (GEFs) for the early endosomal small GTPase RAB35 (MIM 604199) and bind to clathrin and clathrin adaptor protein-2 (AP2; see MIM 601024). Thus, connecdenns link RAB35 activation with the clathrin machinery (Marat and McPherson, 2010 [PubMed 20154091]).[supplied by OMIM, Nov 2010]
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ACMG classification
Classification made for transcript
Verdict is Uncertain_significance. Variant got 4 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.919
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
DENND1B | NM_001195215.2 | c.1163G>A | p.Arg388Gln | missense_variant | 16/23 | ENST00000620048.6 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
DENND1B | ENST00000620048.6 | c.1163G>A | p.Arg388Gln | missense_variant | 16/23 | 5 | NM_001195215.2 | P2 | |
DENND1B | ENST00000367396.7 | c.1163G>A | p.Arg388Gln | missense_variant | 16/16 | 1 | A2 | ||
DENND1B | ENST00000235453.8 | c.1073G>A | p.Arg358Gln | missense_variant | 16/16 | 1 | |||
DENND1B | ENST00000294737.11 | c.988-6326G>A | intron_variant, NMD_transcript_variant | 2 |
Frequencies
GnomAD3 genomes AF: 0.0000132 AC: 2AN: 151846Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000226 AC: 4AN: 177276Hom.: 0 AF XY: 0.0000101 AC XY: 1AN XY: 98938
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GnomAD4 exome AF: 0.0000153 AC: 21AN: 1369978Hom.: 0 Cov.: 31 AF XY: 0.0000147 AC XY: 10AN XY: 678372
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GnomAD4 genome AF: 0.0000132 AC: 2AN: 151846Hom.: 0 Cov.: 32 AF XY: 0.0000270 AC XY: 2AN XY: 74118
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ClinVar
Not reported inComputational scores
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Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Pathogenic
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
LIST_S2
Pathogenic
D;D;D
M_CAP
Uncertain
D
MetaRNN
Pathogenic
D;D;D
MetaSVM
Uncertain
D
MutationAssessor
Uncertain
M;.;M
MutationTaster
Benign
D;D;D
PrimateAI
Uncertain
T
Sift4G
Pathogenic
D;D;D
Polyphen
D;D;D
Vest4
MutPred
Gain of ubiquitination at K391 (P = 0.0414);.;Gain of ubiquitination at K391 (P = 0.0414);
MVP
MPC
0.33
ClinPred
D
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Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at