11-8702644-A-G

Position:

• chr11-8702644-A-G

Variant summary

Our verdict is Benign. Variant got -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. V883M) 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

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

Verdict is Benign. Variant got -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 id is 2641582.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High Homozygotes in GnomAd4 at 2 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DENND2B	NM_213618.2	c.2648T>C	p.Val883Ala	missense_variant	14/20	ENST00000313726.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DENND2B	ENST00000313726.11	c.2648T>C	p.Val883Ala	missense_variant	14/20	1	NM_213618.2	A1

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

GnomAD3 exomes AF: 0.00559 AC: 1403 AN: 251170 Hom.: 11 AF XY: 0.00547 AC XY: 742 AN XY: 135760

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 SAS exome AF: 0.000588

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

Gnomad4 AFR exome AF: 0.000836

Gnomad4 AMR exome AF: 0.00119

Gnomad4 ASJ exome AF: 0.000115

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000719

Gnomad4 FIN exome AF: 0.0231

Gnomad4 NFE exome AF: 0.00655

Gnomad4 OTH exome AF: 0.00414

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

Gnomad4 AFR AF: 0.00144

Gnomad4 AMR AF: 0.000850

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000830

Gnomad4 FIN AF: 0.0216

Gnomad4 NFE AF: 0.00607

Gnomad4 OTH AF: 0.00237

Alfa AF: 0.00583 Hom.: 3

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

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Mar 01, 2023

DENND2B: BS2 -

Computational scores

Source: dbNSFP v4.3

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;T;.;T;T;.
Eigen	Uncertain	0.21
Eigen_PC	Uncertain	0.31
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Benign	0.81	.;.;T;T;T;T;T
MetaRNN	Benign	0.010	T;T;T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.3	.;M;M;.;.;.;.
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D
PrimateAI	Uncertain	0.72	T
PROVEAN	Uncertain	-3.6	D;D;D;D;D;D;D
REVEL	Uncertain	0.38
Sift	Benign	0.10	T;D;D;T;T;T;T
Sift4G	Benign	0.091	T;D;D;T;T;T;T
Polyphen		0.012	B;B;B;.;B;.;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

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

Publications

LitVar

Other links and lift over

dbSNP: rs113126215; hg19: chr11-8724191;