11-8707189-C-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_213618.2(DENND2B):c.2467G>A(p.Ala823Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00138 in 1,613,506 control chromosomes in the GnomAD database, including 39 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0017 (2 hom., cov: 32)
  • Exomes 𝑓: 0.0013 (37 hom.)
• Consequence: DENND2B NM_213618.2 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 3.21

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.009617209).
• BP6: Variant 11-8707189-C-T is Benign according to our data. Variant chr11-8707189-C-T is described in ClinVar as [Benign]. Clinvar id is 769795.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.00174 (265/152340) while in subpopulation EAS AF= 0.0185 (96/5178). AF 95% confidence interval is 0.0155. There are 2 homozygotes in gnomad4. There are 152 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 2 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DENND2B	NM_213618.2	c.2467G>A	p.Ala823Thr	missense_variant	13/20	ENST00000313726.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DENND2B	ENST00000313726.11	c.2467G>A	p.Ala823Thr	missense_variant	13/20	1	NM_213618.2	A1

Frequencies

GnomAD3 genomes AF: 0.00175 AC: 266 AN: 152222 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.000651

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00831

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0185

Gnomad SAS AF: 0.00186

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00287

GnomAD3 exomes AF: 0.00303 AC: 760 AN: 251022 Hom.: 10 AF XY: 0.00246 AC XY: 334 AN XY: 135688

Gnomad AFR exome AF: 0.000369

Gnomad AMR exome AF: 0.0132

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0140

Gnomad SAS exome AF: 0.000785

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000352

Gnomad OTH exome AF: 0.00196

GnomAD4 exome AF: 0.00134 AC: 1956 AN: 1461166 Hom.: 37 Cov.: 31 AF XY: 0.00127 AC XY: 920 AN XY: 726832

Gnomad4 AFR exome AF: 0.000179

Gnomad4 AMR exome AF: 0.0130

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0294

Gnomad4 SAS exome AF: 0.000964

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000324

Gnomad4 OTH exome AF: 0.00134

GnomAD4 genome AF: 0.00174 AC: 265 AN: 152340 Hom.: 2 Cov.: 32 AF XY: 0.00204 AC XY: 152 AN XY: 74506

Gnomad4 AFR AF: 0.000649

Gnomad4 AMR AF: 0.00823

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.0185

Gnomad4 SAS AF: 0.00186

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00284

Alfa AF: 0.000875 Hom.: 1

Bravo AF: 0.00219

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00268 AC: 325

Asia WGS AF: 0.00577 AC: 20 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Dec 31, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.48
BayesDel_addAF	Benign	-0.35	T
BayesDel_noAF	Benign	-0.24
Cadd	Uncertain	24
Dann	Uncertain	1.0
Eigen	Benign	-0.14
Eigen_PC	Benign	0.0066
FATHMM_MKL	Uncertain	0.93	D
MetaRNN	Benign	0.0096	T;T;T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D
PrimateAI	Uncertain	0.78	T
PROVEAN	Benign	-0.99	N;N;N;N;N;N;N;N
REVEL	Benign	0.19
Sift	Benign	0.18	T;T;T;T;T;T;T;T
Sift4G	Benign	0.25	T;T;T;T;T;T;T;.
Polyphen		0.018	B;B;B;.;P;.;B;.
Vest4		0.59
MVP		0.51
MPC		1.3
ClinPred		0.042	T
GERP RS		5.1
Varity_R		0.18
gMVP		0.45

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs149402828; hg19: chr11-8728736; COSMIC: COSV100567176; COSMIC: COSV100567176;