11-8776186-A-ACACACACC

Variant names:

• chr11-8776186-A-ACACACACC
• rs761084725
• NM_213618.2:c.-25-25462_-25-25461insGGTGTGTG

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BS1 BS2

The NM_213618.2(DENND2B):​c.-25-25462_-25-25461insGGTGTGTG variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00458 in 440,064 control chromosomes in the GnomAD database, including 19 homozygotes. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.0055 (10 hom., cov: 32)
  • Exomes 𝑓: 0.0041 (9 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: Benign. The variant received -8 ACMG points.

• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.00554 (795/143436) while in subpopulation SAS AF = 0.0338 (149/4412). AF 95% confidence interval is 0.0294. There are 10 homozygotes in GnomAd4. There are 409 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 10 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_-25-25461insGGTGTGTG		intron	N/A	NP_998783.1	P78524-1
	DENND2B	NM_001376495.1		c.-25-25462_-25-25461insGGTGTGTG		intron	N/A	NP_001363424.1	P78524-1
	DENND2B	NM_001376496.1		c.-25-25462_-25-25461insGGTGTGTG		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_-25-25461insGGTGTGTG		intron	N/A	ENSP00000319678.6	P78524-1
	DENND2B	ENST00000534127.5	TSL:1	c.-25-25462_-25-25461insGGTGTGTG		intron	N/A	ENSP00000433528.1	P78524-1
	DENND2B	ENST00000526757.5	TSL:1	c.-25-25462_-25-25461insGGTGTGTG		intron	N/A	ENSP00000435097.1	P78524-2

Frequencies

GnomAD3 genomes AF: 0.00557 AC: 798 AN: 143318 Hom.: 10 Cov.: 32

Gnomad AFR AF: 0.000870

Gnomad AMI AF: 0.00114

Gnomad AMR AF: 0.00357

Gnomad ASJ AF: 0.00743

Gnomad EAS AF: 0.000199

Gnomad SAS AF: 0.0342

Gnomad FIN AF: 0.000606

Gnomad MID AF: 0.0417

Gnomad NFE AF: 0.00788

Gnomad OTH AF: 0.00670

GnomAD4 exome AF: 0.00412 AC: 1222 AN: 296628 Hom.: 9 Cov.: 0 AF XY: 0.00469 AC XY: 789 AN XY: 168306

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

African (AFR) AF: 0.000235 AC: 2 AN: 8516

American (AMR) AF: 0.00127 AC: 34 AN: 26868

Ashkenazi Jewish (ASJ) AF: 0.00258 AC: 27 AN: 10476

East Asian (EAS) AF: 0.00 AC: 0 AN: 9214

South Asian (SAS) AF: 0.0108 AC: 611 AN: 56794

European-Finnish (FIN) AF: 0.000406 AC: 5 AN: 12310

Middle Eastern (MID) AF: 0.0121 AC: 31 AN: 2558

European-Non Finnish (NFE) AF: 0.00303 AC: 472 AN: 155928

Other (OTH) AF: 0.00286 AC: 40 AN: 13964

⚠️ 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: 0.00554 AC: 795 AN: 143436 Hom.: 10 Cov.: 32 AF XY: 0.00584 AC XY: 409 AN XY: 70060

African (AFR) AF: 0.000868 AC: 34 AN: 39188

American (AMR) AF: 0.00356 AC: 52 AN: 14598

Ashkenazi Jewish (ASJ) AF: 0.00743 AC: 24 AN: 3232

East Asian (EAS) AF: 0.000200 AC: 1 AN: 5012

South Asian (SAS) AF: 0.0338 AC: 149 AN: 4412

European-Finnish (FIN) AF: 0.000606 AC: 6 AN: 9898

Middle Eastern (MID) AF: 0.0414 AC: 11 AN: 266

European-Non Finnish (NFE) AF: 0.00788 AC: 504 AN: 63986

Other (OTH) AF: 0.00662 AC: 13 AN: 1964

Alfa AF: 0.00174 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;