Genetic Variant DENND2B:c.-25-25462_-25-25461insGGTG (chr11-8776186-A-ACACC) – 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_-25-25461insGGTG variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00012 in 442,960 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.00019 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000087 ( 0 hom. )

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_-25-25461insGGTG	intron	N/A	NP_998783.1	P78524-1
DENND2B	NM_001376495.1		c.-25-25462_-25-25461insGGTG	intron	N/A	NP_001363424.1	P78524-1
DENND2B	NM_001376496.1		c.-25-25462_-25-25461insGGTG	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_-25-25461insGGTG	intron	N/A	ENSP00000319678.6	P78524-1
DENND2B	ENST00000534127.5	TSL:1	c.-25-25462_-25-25461insGGTG	intron	N/A	ENSP00000433528.1	P78524-1
DENND2B	ENST00000526757.5	TSL:1	c.-25-25462_-25-25461insGGTG	intron	N/A	ENSP00000435097.1	P78524-2

Frequencies

GnomAD3 genomes

AF:

0.000188

AC:

AN:

143334

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000686

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:

0.000406

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.0000868

AC:

AN:

299626

Hom.:

Cov.:

AF XY:

0.0000880

AC XY:

AN XY:

170420

show subpopulations

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

African (AFR)

AF:

0.00

AC:

AN:

8524

American (AMR)

AF:

0.00

AC:

AN:

26932

Ashkenazi Jewish (ASJ)

AF:

0.0000950

AC:

AN:

10524

East Asian (EAS)

AF:

0.00

AC:

AN:

9214

South Asian (SAS)

AF:

0.0000342

AC:

AN:

58468

European-Finnish (FIN)

AF:

0.00

AC:

AN:

12320

Middle Eastern (MID)

AF:

0.00

AC:

AN:

2576

European-Non Finnish (NFE)

AF:

0.000147

AC:

AN:

156994

Other (OTH)

AF:

0.00

AC:

AN:

14074

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.0000000516799), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.362

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome 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

GnomAD4 genome

AF:

0.000188

AC:

AN:

143334

Hom.:

Cov.:

AF XY:

0.000157

AC XY:

AN XY:

69936

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

39076

American (AMR)

AF:

0.0000686

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:

0.000406

AC:

AN:

64002

Other (OTH)

AF:

0.00

AC:

AN:

1940

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.468

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

Alfa

AF:

0.00

Hom.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

-0.46

Mutation Taster

=100/0

polymorphism

(source)

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

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over