chr11-8776186-A-ACACACACACACACACACC

Variant names:

• chr11-8776186-A-ACACACACACACACACACC
• rs761084725
• NM_213618.2:c.-25-25462_-25-25461insGGTGTGTGTGTGTGTGTG

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BS2

The NM_213618.2(DENND2B):​c.-25-25462_-25-25461insGGTGTGTGTGTGTGTGTG variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00119 in 442,174 control chromosomes in the GnomAD database, including 6 homozygotes. 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 0.0020 (4 hom., cov: 32)
  • Exomes 𝑓: 0.00078 (2 hom.)
• Consequence: DENND2B NM_213618.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.461
• Publications: 0 publications found

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

ACMG classification

Our verdict: Likely_benign. The variant received -4 ACMG points.

• BS2: High Homozygotes in GnomAd4 at 4 gene

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

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

Ensembl Transcripts

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

Frequencies

GnomAD3 genomes AF: 0.00204 AC: 292 AN: 143306 Hom.: 4 Cov.: 32

Gnomad AFR AF: 0.000461

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00124

Gnomad ASJ AF: 0.0238

Gnomad EAS AF: 0.000597

Gnomad SAS AF: 0.00226

Gnomad FIN AF: 0.000202

Gnomad MID AF: 0.0278

Gnomad NFE AF: 0.00227

Gnomad OTH AF: 0.00567

GnomAD4 exome AF: 0.000783 AC: 234 AN: 298750 Hom.: 2 Cov.: 0 AF XY: 0.000700 AC XY: 119 AN XY: 169906

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

African (AFR) AF: 0.000117 AC: 1 AN: 8520

American (AMR) AF: 0.000223 AC: 6 AN: 26902

Ashkenazi Jewish (ASJ) AF: 0.00607 AC: 63 AN: 10372

East Asian (EAS) AF: 0.000109 AC: 1 AN: 9214

South Asian (SAS) AF: 0.000308 AC: 18 AN: 58362

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 12312

Middle Eastern (MID) AF: 0.00117 AC: 3 AN: 2568

European-Non Finnish (NFE) AF: 0.000792 AC: 124 AN: 156484

Other (OTH) AF: 0.00128 AC: 18 AN: 14016

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.00203 AC: 291 AN: 143424 Hom.: 4 Cov.: 32 AF XY: 0.00191 AC XY: 134 AN XY: 70050

African (AFR) AF: 0.000459 AC: 18 AN: 39184

American (AMR) AF: 0.00123 AC: 18 AN: 14596

Ashkenazi Jewish (ASJ) AF: 0.0238 AC: 77 AN: 3230

East Asian (EAS) AF: 0.000599 AC: 3 AN: 5012

South Asian (SAS) AF: 0.00226 AC: 10 AN: 4418

European-Finnish (FIN) AF: 0.000202 AC: 2 AN: 9898

Middle Eastern (MID) AF: 0.0263 AC: 7 AN: 266

European-Non Finnish (NFE) AF: 0.00227 AC: 145 AN: 63976

Other (OTH) AF: 0.00560 AC: 11 AN: 1964

Alfa AF: 0.00218 Hom.: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.46
Mutation Taster		=100/0	polymorphism

Splicing

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

Other links and lift over

dbSNP: rs761084725; hg19: chr11-8797733;