11-8695456-C-T

Variant names:

• chr11-8695456-C-T
• rs2270956
• NM_213618.2:c.3379+7G>A

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 14 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]

ENSG00000254665 (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

Our verdict: Benign. The variant received -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 VariationId 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.

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.3379+7G>A		splice_region intron	N/A	NP_998783.1	P78524-1
	DENND2B	NM_001376495.1		c.3379+7G>A		splice_region intron	N/A	NP_001363424.1	P78524-1
	DENND2B	NM_001376496.1		c.3379+7G>A		splice_region 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.3379+7G>A		splice_region intron	N/A	ENSP00000319678.6	P78524-1
	DENND2B	ENST00000534127.5	TSL:1	c.3379+7G>A		splice_region intron	N/A	ENSP00000433528.1	P78524-1
	DENND2B	ENST00000526757.5	TSL:1	c.2119+7G>A		splice_region intron	N/A	ENSP00000435097.1	P78524-2

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

GnomAD2 exomes AF: 0.434 AC: 108721 AN: 250794 AF XY: 0.437

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 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

African (AFR) AF: 0.151 AC: 5049 AN: 33434

American (AMR) AF: 0.423 AC: 18913 AN: 44688

Ashkenazi Jewish (ASJ) AF: 0.385 AC: 10035 AN: 26092

East Asian (EAS) AF: 0.429 AC: 17028 AN: 39648

South Asian (SAS) AF: 0.428 AC: 36897 AN: 86188

European-Finnish (FIN) AF: 0.500 AC: 26392 AN: 52742

Middle Eastern (MID) AF: 0.365 AC: 2103 AN: 5754

European-Non Finnish (NFE) AF: 0.475 AC: 526366 AN: 1108558

Other (OTH) AF: 0.440 AC: 26512 AN: 60264

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

African (AFR) AF: 0.165 AC: 6858 AN: 41476

American (AMR) AF: 0.410 AC: 6260 AN: 15266

Ashkenazi Jewish (ASJ) AF: 0.384 AC: 1330 AN: 3468

East Asian (EAS) AF: 0.428 AC: 2215 AN: 5178

South Asian (SAS) AF: 0.429 AC: 2070 AN: 4826

European-Finnish (FIN) AF: 0.499 AC: 5271 AN: 10556

Middle Eastern (MID) AF: 0.429 AC: 126 AN: 294

European-Non Finnish (NFE) AF: 0.471 AC: 31986 AN: 67964

Other (OTH) AF: 0.375 AC: 793 AN: 2116

Alfa AF: 0.416 Hom.: 9937

Bravo AF: 0.361

Asia WGS AF: 0.370 AC: 1289 AN: 3478

EpiCase AF: 0.457

EpiControl AF: 0.462

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.74
CADD	Benign	6.2
DANN	Benign	0.76
PhyloP100		-0.056
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

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