11-8711231-G-C

Position:

• chr11-8711231-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_213618.2(DENND2B):​c.2173C>G​(p.Leu725Val) variant causes a missense, splice region change. The variant was absent in control chromosomes in GnomAD project. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: DENND2B NM_213618.2 missense, splice_region
• Scores: Splicing: ADA: 0.01512
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.67

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 Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DENND2B	NM_213618.2	c.2173C>G	p.Leu725Val	missense_variant, splice_region_variant	10/20	ENST00000313726.11	NP_998783.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DENND2B	ENST00000313726.11	c.2173C>G	p.Leu725Val	missense_variant, splice_region_variant	10/20	1	NM_213618.2	ENSP00000319678.6

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

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

Aug 15, 2023

The c.2173C>G (p.L725V) alteration is located in exon 13 (coding exon 9) of the ST5 gene. This alteration results from a C to G substitution at nucleotide position 2173, causing the leucine (L) at amino acid position 725 to be replaced by a valine (V). 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	Benign	0.30
BayesDel_addAF	Uncertain	0.071	D
BayesDel_noAF	Benign	-0.14
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.043	.;T;T;.;T;.;.;T
Eigen	Uncertain	0.43
Eigen_PC	Uncertain	0.42
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.85	.;.;T;T;T;T;T;T
M_CAP	Benign	0.038	D
MetaRNN	Uncertain	0.48	T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.87	T
MutationAssessor	Uncertain	2.2	.;M;M;.;.;.;.;.
PrimateAI	Uncertain	0.73	T
PROVEAN	Benign	-2.0	N;N;N;N;N;N;N;N
REVEL	Benign	0.19
Sift	Benign	0.20	T;T;T;T;T;T;T;T
Sift4G	Benign	0.38	T;T;T;T;T;T;.;.
Polyphen		0.86	P;P;P;.;D;P;.;.
Vest4		0.64
MutPred		0.43		.;Loss of ubiquitination at K724 (P = 0.1037);Loss of ubiquitination at K724 (P = 0.1037);.;.;.;.;.;
MVP		0.56
MPC		1.7
ClinPred		0.98	D
GERP RS		4.2
Varity_R		0.22
gMVP		0.30

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.015
dbscSNV1_RF	Benign	0.34
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

No publications associated with this variant yet.

Other links and lift over

hg19: chr11-8732778;