11-8707189-C-T

Position:

• chr11-8707189-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong 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, multiple submitters, no conflicts B:2
• 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]

DENND2B (HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 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_multiple_submitters_no_conflicts, 2 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 GnomAd4 at 2 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DENND2B	NM_213618.2	c.2467G>A	p.Ala823Thr	missense_variant	13/20	ENST00000313726.11	NP_998783.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DENND2B	ENST00000313726.11	c.2467G>A	p.Ala823Thr	missense_variant	13/20	1	NM_213618.2	ENSP00000319678.6

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:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	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
DEOGEN2	Benign	0.028	.;T;T;.;T;T;.;.
Eigen	Benign	-0.14
Eigen_PC	Benign	0.0066
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.89	.;.;D;D;D;D;D;D
MetaRNN	Benign	0.0096	T;T;T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.34	.;N;N;.;.;.;.;.
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;