Variant 1-197595260-C-G details in Genebe, Genetics Data Aggregator

Variant summary

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

The NM_001195215.2(DENND1B):c.995G>C(p.Arg332Thr) variant causes a missense change. The variant allele was found at a frequency of 0.00000205 in 1,461,208 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: not found (cov: 32)

Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

DENND1B
NM_001195215.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 5.82

Variant links:

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]

DENND1B links:

DENND1B (HGNC:):

DENND1B links:

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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, 0.82

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DENND1B	NM_001195215.2 linkuse as main transcript	c.995G>C	p.Arg332Thr	missense_variant	14/23	ENST00000620048.6	NP_001182144.1	Q6P3S1-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
DENND1B	ENST00000620048.6 linkuse as main transcript	c.995G>C	p.Arg332Thr	missense_variant	14/23	5	NM_001195215.2	ENSP00000479816.1	Q6P3S1-1
DENND1B	ENST00000367396.7 linkuse as main transcript	c.995G>C	p.Arg332Thr	missense_variant	14/16	1		ENSP00000356366.3	Q6P3S1-5
DENND1B	ENST00000235453.8 linkuse as main transcript	c.905G>C	p.Arg302Thr	missense_variant	14/16	1		ENSP00000235453.4	Q6P3S1-4
DENND1B	ENST00000294737.11 linkuse as main transcript	n.935G>C		non_coding_transcript_exon_variant	13/20	2		ENSP00000294737.7	B3KR95

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000402

AC:

AN:

249020

Hom.:

AF XY:

0.00000740

AC XY:

AN XY:

135060

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:

0.00

Gnomad NFE exome

AF:

0.00000886

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000205

AC:

AN:

1461208

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

726906

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:

9.00e-7

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

Cov.:

ExAC

AF:

0.00000828

AC:

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

Jun 03, 2024

The c.995G>C (p.R332T) alteration is located in exon 14 (coding exon 14) of the DENND1B gene. This alteration results from a G to C substitution at nucleotide position 995, causing the arginine (R) at amino acid position 332 to be replaced by a threonine (T). 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

Pathogenic

0.59

BayesDel_addAF

Pathogenic

0.23

BayesDel_noAF

Uncertain

0.10

CADD

Pathogenic

DANN

Benign

0.97

Eigen

Uncertain

0.55

Eigen_PC

Uncertain

0.63

FATHMM_MKL

Uncertain

0.96

LIST_S2

Uncertain

0.96

D;D;D

M_CAP

Benign

0.025

MetaRNN

Pathogenic

0.82

D;D;D

MetaSVM

Benign

-0.74

MutationAssessor

Uncertain

2.5

M;.;M

PrimateAI

Uncertain

0.76

PROVEAN

Uncertain

-4.2

.;D;D

REVEL

Uncertain

0.37

Sift

Uncertain

0.0080

.;D;D

Sift4G

Uncertain

0.0060

D;D;D

Polyphen

0.65

P;P;P

Vest4

0.90

MutPred

0.67

Loss of MoRF binding (P = 0.0104);.;Loss of MoRF binding (P = 0.0104);

MVP

0.41

MPC

0.35

ClinPred

0.93

GERP RS

6.1

Varity_R

0.87

gMVP

0.74

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