Genetic Variant DENND2B:c.-25-25462_-25-25461insGGGGTGTGTGTGTG (chr11-8776186-A-ACACACACACACCCC) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 0P and 0B.

The NM_213618.2(DENND2B):c.-25-25462_-25-25461insGGGGTGTGTGTGTG variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000488 in 143,332 control chromosomes in the GnomAD database, with no homozygous occurrence. It is difficult to determine the true allele frequency of this variant because it is of type INS_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.000049 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

DENND2B
NM_213618.2 intron

Scores

Not classified

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.461

Publications

0 publications found

Variant links:

Genes affected

DENND2B (HGNC:11350): (DENN domain containing 2B) This gene was identified by its ability to suppress the tumorigenicity of Hela cells in nude mice. The protein encoded by this gene contains a C-terminal region that shares similarity with the Rab 3 family of small GTP binding proteins. This protein preferentially binds to the SH3 domain of c-Abl kinase, and acts as a regulator of MAPK1/ERK2 kinase, which may contribute to its ability to reduce the tumorigenic phenotype in cells. Three alternatively spliced transcript variants of this gene encoding distinct isoforms are identified. [provided by RefSeq, Jul 2008]

DENND2B links:

DENND2B-AS1 (HGNC:56176): (DENND2B antisense RNA 1)

DENND2B-AS1 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_213618.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
DENND2B	NM_213618.2	MANE Select	c.-25-25462_-25-25461insGGGGTGTGTGTGTG	intron	N/A	NP_998783.1	P78524-1
DENND2B	NM_001376495.1		c.-25-25462_-25-25461insGGGGTGTGTGTGTG	intron	N/A	NP_001363424.1	P78524-1
DENND2B	NM_001376496.1		c.-25-25462_-25-25461insGGGGTGTGTGTGTG	intron	N/A	NP_001363425.1	P78524-1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
DENND2B	ENST00000313726.11	TSL:1 MANE Select	c.-25-25462_-25-25461insGGGGTGTGTGTGTG	intron	N/A	ENSP00000319678.6	P78524-1
DENND2B	ENST00000534127.5	TSL:1	c.-25-25462_-25-25461insGGGGTGTGTGTGTG	intron	N/A	ENSP00000433528.1	P78524-1
DENND2B	ENST00000526757.5	TSL:1	c.-25-25462_-25-25461insGGGGTGTGTGTGTG	intron	N/A	ENSP00000435097.1	P78524-2

Frequencies

GnomAD3 genomes

AF:

0.0000488

AC:

AN:

143332

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000179

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

Data not reliable, filtered out with message: AC0;AS_VQSR

AF:

0.00

AC:

AN:

299698

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

170464

African (AFR)

AF:

0.00

AC:

AN:

8524

American (AMR)

AF:

0.00

AC:

AN:

26940

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

10524

East Asian (EAS)

AF:

0.00

AC:

AN:

9214

South Asian (SAS)

AF:

0.00

AC:

AN:

58476

European-Finnish (FIN)

AF:

0.00

AC:

AN:

12320

Middle Eastern (MID)

AF:

0.00

AC:

AN:

2576

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

157044

Other (OTH)

AF:

0.00

AC:

AN:

14080

GnomAD4 genome

AF:

0.0000488

AC:

AN:

143332

Hom.:

Cov.:

AF XY:

0.0000429

AC XY:

AN XY:

69934

show subpopulations

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.000179

AC:

AN:

39074

American (AMR)

AF:

0.00

AC:

AN:

14574

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3232

East Asian (EAS)

AF:

0.00

AC:

AN:

5024

South Asian (SAS)

AF:

0.00

AC:

AN:

4420

European-Finnish (FIN)

AF:

0.00

AC:

AN:

9898

Middle Eastern (MID)

AF:

0.00

AC:

AN:

288

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

64002

Other (OTH)

AF:

0.00

AC:

AN:

1940

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.346

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

-0.46

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over