11-8707806-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_213618.2(DENND2B):c.2401C>T(p.Arg801Cys) variant causes a missense change. The variant allele was found at a frequency of 0.000018 in 1,611,450 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000019 (0 hom.)
• Consequence: DENND2B NM_213618.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.93

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 Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.862

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DENND2B	NM_213618.2	c.2401C>T	p.Arg801Cys	missense_variant	12/20	ENST00000313726.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DENND2B	ENST00000313726.11	c.2401C>T	p.Arg801Cys	missense_variant	12/20	1	NM_213618.2	A1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152222 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000122 AC: 3 AN: 245646 Hom.: 0 AF XY: 0.0000151 AC XY: 2 AN XY: 132708

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000552

Gnomad SAS exome AF: 0.0000337

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000899

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000192 AC: 28 AN: 1459228 Hom.: 0 Cov.: 31 AF XY: 0.0000138 AC XY: 10 AN XY: 725572

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000702

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000180

Gnomad4 OTH exome AF: 0.0000332

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152222 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74362

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000329 Hom.: 0

Bravo AF: 0.0000189

ExAC AF: 0.0000165 AC: 2

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 17, 2023

The c.2401C>T (p.R801C) alteration is located in exon 15 (coding exon 11) of the ST5 gene. This alteration results from a C to T substitution at nucleotide position 2401, causing the arginine (R) at amino acid position 801 to be replaced by a cysteine (C). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.70
BayesDel_addAF	Uncertain	0.053	T
BayesDel_noAF	Uncertain	0.010
Cadd	Pathogenic	27
Dann	Uncertain	0.99
Eigen	Uncertain	0.19
Eigen_PC	Uncertain	0.28
FATHMM_MKL	Uncertain	0.95	D
M_CAP	Benign	0.028	D
MetaRNN	Pathogenic	0.86	D;D;D;D;D;D;D
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D
PrimateAI	Pathogenic	0.86	D
PROVEAN	Pathogenic	-7.3	D;D;D;D;D;D;D
REVEL	Uncertain	0.42
Sift	Benign	0.17	T;T;T;T;T;T;T
Sift4G	Benign	0.14	T;T;T;T;T;T;.
Polyphen		0.055	B;B;B;.;D;B;.
Vest4		0.79
MutPred		0.82		.;Gain of catalytic residue at L802 (P = 0.0301);Gain of catalytic residue at L802 (P = 0.0301);.;.;.;.;
MVP		0.53
MPC		1.8
ClinPred		0.99	D
GERP RS		4.3
Varity_R		0.50
gMVP		0.83

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs774224264; hg19: chr11-8729353;