11-8695456-C-T

Position:

• chr11-8695456-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_213618.2(DENND2B):​c.3379+7G>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.452 in 1,609,420 control chromosomes in the GnomAD database, including 168,546 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.38 (12200 hom., cov: 32)
  • Exomes 𝑓: 0.46 (156346 hom.)
• Consequence: DENND2B NM_213618.2 splice_region, intron
• Scores: Splicing: ADA: 0.0002293
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.0560

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]

(HGNC:):

RPL27A (HGNC:10329): (ribosomal protein L27a) Ribosomes, the organelles that catalyze protein synthesis, consist of a small 40S subunit and a large 60S subunit. Together these subunits are composed of 4 RNA species and approximately 80 structurally distinct proteins. This gene encodes a ribosomal protein that is a component of the 60S subunit. The protein belongs to the L15P family of ribosomal proteins. It is located in the cytoplasm. Variable expression of this gene in colorectal cancers compared to adjacent normal tissues has been observed, although no correlation between the level of expression and the severity of the disease has been found. As is typical for genes encoding ribosomal proteins, multiple processed pseudogenes derived from this gene are dispersed through the genome. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.74).
• BP6: Variant 11-8695456-C-T is Benign according to our data. Variant chr11-8695456-C-T is described in ClinVar as [Benign]. Clinvar id is 1236934.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.466 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DENND2B	NM_213618.2	c.3379+7G>A		splice_region_variant, intron_variant		ENST00000313726.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DENND2B	ENST00000313726.11	c.3379+7G>A		splice_region_variant, intron_variant		1	NM_213618.2	A1
	ENST00000529883.1	n.605-1012C>T		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes AF: 0.378 AC: 57388 AN: 151934 Hom.: 12193 Cov.: 32

Gnomad AFR AF: 0.166

Gnomad AMI AF: 0.528

Gnomad AMR AF: 0.410

Gnomad ASJ AF: 0.384

Gnomad EAS AF: 0.429

Gnomad SAS AF: 0.427

Gnomad FIN AF: 0.499

Gnomad MID AF: 0.437

Gnomad NFE AF: 0.471

Gnomad OTH AF: 0.378

GnomAD3 exomes AF: 0.434 AC: 108721 AN: 250794 Hom.: 24416 AF XY: 0.437 AC XY: 59251 AN XY: 135600

Gnomad AFR exome AF: 0.158

Gnomad AMR exome AF: 0.428

Gnomad ASJ exome AF: 0.383

Gnomad EAS exome AF: 0.417

Gnomad SAS exome AF: 0.428

Gnomad FIN exome AF: 0.507

Gnomad NFE exome AF: 0.469

Gnomad OTH exome AF: 0.439

GnomAD4 exome AF: 0.459 AC: 669295 AN: 1457368 Hom.: 156346 Cov.: 32 AF XY: 0.459 AC XY: 332548 AN XY: 725230

Gnomad4 AFR exome AF: 0.151

Gnomad4 AMR exome AF: 0.423

Gnomad4 ASJ exome AF: 0.385

Gnomad4 EAS exome AF: 0.429

Gnomad4 SAS exome AF: 0.428

Gnomad4 FIN exome AF: 0.500

Gnomad4 NFE exome AF: 0.475

Gnomad4 OTH exome AF: 0.440

GnomAD4 genome AF: 0.377 AC: 57388 AN: 152052 Hom.: 12200 Cov.: 32 AF XY: 0.380 AC XY: 28217 AN XY: 74314

Gnomad4 AFR AF: 0.165

Gnomad4 AMR AF: 0.410

Gnomad4 ASJ AF: 0.384

Gnomad4 EAS AF: 0.428

Gnomad4 SAS AF: 0.429

Gnomad4 FIN AF: 0.499

Gnomad4 NFE AF: 0.471

Gnomad4 OTH AF: 0.375

Alfa AF: 0.416 Hom.: 8885

Bravo AF: 0.361

Asia WGS AF: 0.370 AC: 1289 AN: 3478

EpiCase AF: 0.457

EpiControl AF: 0.462

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 28, 2019	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.74
CADD	Benign	6.2
DANN	Benign	0.76
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00023
dbscSNV1_RF	Benign	0.026
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs2270956; hg19: chr11-8717003; COSMIC: COSV58202126; COSMIC: COSV58202126;