rs113126215

Variant names:

• chr11-8702644-A-G
• rs113126215
• NM_213618.2:c.2648T>C

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

The NM_213618.2(DENND2B):​c.2648T>C​(p.Val883Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00597 in 1,613,966 control chromosomes in the GnomAD database, including 44 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V883E) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0048 (2 hom., cov: 32)
  • Exomes 𝑓: 0.0061 (42 hom.)
• Consequence: DENND2B NM_213618.2 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 7.57
• Publications: 8 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]

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 -10 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.01018852).
• BP6: Variant 11-8702644-A-G is Benign according to our data. Variant chr11-8702644-A-G is described in ClinVar as Likely_benign. ClinVar VariationId is 2641582.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High Homozygotes in GnomAd4 at 2 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.2648T>C	p.Val883Ala	missense	Exon 14 of 20	NP_998783.1	P78524-1
	DENND2B	NM_001376495.1		c.2648T>C	p.Val883Ala	missense	Exon 18 of 24	NP_001363424.1	P78524-1
	DENND2B	NM_001376496.1		c.2648T>C	p.Val883Ala	missense	Exon 16 of 22	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.2648T>C	p.Val883Ala	missense	Exon 14 of 20	ENSP00000319678.6	P78524-1
	DENND2B	ENST00000534127.5	TSL:1	c.2648T>C	p.Val883Ala	missense	Exon 17 of 23	ENSP00000433528.1	P78524-1
	DENND2B	ENST00000526757.5	TSL:1	c.1388T>C	p.Val463Ala	missense	Exon 13 of 19	ENSP00000435097.1	P78524-2

Frequencies

GnomAD3 genomes AF: 0.00476 AC: 724 AN: 152174 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.00145

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000851

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000829

Gnomad FIN AF: 0.0216

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00607

Gnomad OTH AF: 0.00239

GnomAD2 exomes AF: 0.00559 AC: 1403 AN: 251170 AF XY: 0.00547

Gnomad AFR exome AF: 0.00129

Gnomad AMR exome AF: 0.00124

Gnomad ASJ exome AF: 0.0000992

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0202

Gnomad NFE exome AF: 0.00757

Gnomad OTH exome AF: 0.00424

GnomAD4 exome AF: 0.00610 AC: 8915 AN: 1461674 Hom.: 42 Cov.: 31 AF XY: 0.00587 AC XY: 4271 AN XY: 727136

African (AFR) AF: 0.000836 AC: 28 AN: 33480

American (AMR) AF: 0.00119 AC: 53 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.000115 AC: 3 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.000719 AC: 62 AN: 86258

European-Finnish (FIN) AF: 0.0231 AC: 1231 AN: 53212

Middle Eastern (MID) AF: 0.000347 AC: 2 AN: 5768

European-Non Finnish (NFE) AF: 0.00655 AC: 7286 AN: 1112004

Other (OTH) AF: 0.00414 AC: 250 AN: 60394

GnomAD4 genome AF: 0.00475 AC: 724 AN: 152292 Hom.: 2 Cov.: 32 AF XY: 0.00525 AC XY: 391 AN XY: 74468

African (AFR) AF: 0.00144 AC: 60 AN: 41584

American (AMR) AF: 0.000850 AC: 13 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5160

South Asian (SAS) AF: 0.000830 AC: 4 AN: 4820

European-Finnish (FIN) AF: 0.0216 AC: 229 AN: 10624

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00607 AC: 413 AN: 68014

Other (OTH) AF: 0.00237 AC: 5 AN: 2114

Alfa AF: 0.00593 Hom.: 10

Bravo AF: 0.00338

TwinsUK AF: 0.00539 AC: 20

ALSPAC AF: 0.00467 AC: 18

ESP6500AA AF: 0.00204 AC: 9

ESP6500EA AF: 0.00559 AC: 48

ExAC AF: 0.00610 AC: 741

EpiCase AF: 0.00622

EpiControl AF: 0.00569

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.35
BayesDel_addAF	Benign	-0.29	T
BayesDel_noAF	Benign	-0.18
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Benign	0.15	T
Eigen	Uncertain	0.21
Eigen_PC	Uncertain	0.31
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Benign	0.81	T
MetaRNN	Benign	0.010	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.3	M
PhyloP100		7.6
PrimateAI	Uncertain	0.72	T
PROVEAN	Uncertain	-3.6	D
REVEL	Uncertain	0.38
Sift	Benign	0.10	T
Sift4G	Benign	0.091	T
Polyphen		0.012	B
Vest4		0.57
MVP		0.51
MPC		1.5
ClinPred		0.045	T
GERP RS		4.7
Varity_R		0.42
gMVP		0.71
Mutation Taster		=97/3	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
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: rs113126215; hg19: chr11-8724191;