Genetic Variant DENND2B:c.-25-25461_-25-25460insTGTGTGT (chr11-8776185-C-CACACACA) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_213618.2(DENND2B):c.-25-25461_-25-25460insTGTGTGT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000398 in 452,450 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 0.000053 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000033 ( 0 hom. )

Consequence

DENND2B
NM_213618.2 intron

Scores

Not classified

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.449

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 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

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.-25-25461_-25-25460insTGTGTGT	intron	N/A	NP_998783.1	P78524-1
DENND2B	NM_001376495.1		c.-25-25461_-25-25460insTGTGTGT	intron	N/A	NP_001363424.1	P78524-1
DENND2B	NM_001376496.1		c.-25-25461_-25-25460insTGTGTGT	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.-25-25461_-25-25460insTGTGTGT	intron	N/A	ENSP00000319678.6	P78524-1
DENND2B	ENST00000534127.5	TSL:1	c.-25-25461_-25-25460insTGTGTGT	intron	N/A	ENSP00000433528.1	P78524-1
DENND2B	ENST00000526757.5	TSL:1	c.-25-25461_-25-25460insTGTGTGT	intron	N/A	ENSP00000435097.1	P78524-2

Frequencies

GnomAD3 genomes

AF:

0.0000531

AC:

AN:

150800

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

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:

0.000119

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000473

AC:

AN:

126910

AF XY:

0.0000432

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.000380

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000641

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000332

AC:

AN:

301650

Hom.:

Cov.:

AF XY:

0.0000466

AC XY:

AN XY:

171658

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:

8574

American (AMR)

AF:

0.0000368

AC:

AN:

27166

Ashkenazi Jewish (ASJ)

AF:

0.000186

AC:

AN:

10752

East Asian (EAS)

AF:

0.00

AC:

AN:

9212

South Asian (SAS)

AF:

0.0000169

AC:

AN:

59064

European-Finnish (FIN)

AF:

0.00

AC:

AN:

12340

Middle Eastern (MID)

AF:

0.00

AC:

AN:

2718

European-Non Finnish (NFE)

AF:

0.0000381

AC:

AN:

157652

Other (OTH)

AF:

0.00

AC:

AN:

14172

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.0315366), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.390

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:

0.0000531

AC:

AN:

150800

Hom.:

Cov.:

AF XY:

0.0000543

AC XY:

AN XY:

73644

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41164

American (AMR)

AF:

0.00

AC:

AN:

15188

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3460

East Asian (EAS)

AF:

0.00

AC:

AN:

5156

South Asian (SAS)

AF:

0.00

AC:

AN:

4750

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10502

Middle Eastern (MID)

AF:

0.00

AC:

AN:

314

European-Non Finnish (NFE)

AF:

0.000119

AC:

AN:

67296

Other (OTH)

AF:

0.00

AC:

AN:

2064

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.537

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

-0.45

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