1-114587737-G-C

Position:

• chr1-114587737-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_001256404.2(DENND2C):​c.2647C>G​(p.Leu883Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: DENND2C NM_001256404.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.60

Genes affected

DENND2C (HGNC:24748): (DENN domain containing 2C) Enables guanyl-nucleotide exchange factor activity. Predicted to be involved in regulation of catalytic activity. Located in nucleoplasm. [provided by Alliance of Genome Resources, Apr 2022]

DENND2C (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.81

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DENND2C	NM_001256404.2	c.2647C>G	p.Leu883Val	missense_variant	19/21	ENST00000393274.6	NP_001243333.1
DENND2C	NM_198459.4	c.2476C>G	p.Leu826Val	missense_variant	16/18		NP_940861.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DENND2C	ENST00000393274.6	c.2647C>G	p.Leu883Val	missense_variant	19/21	5	NM_001256404.2	ENSP00000376955.1
DENND2C	ENST00000481894.1	n.2231C>G		non_coding_transcript_exon_variant	17/18	1
DENND2C	ENST00000393276.7	c.2476C>G	p.Leu826Val	missense_variant	16/18	5		ENSP00000376957.3
DENND2C	ENST00000495031.5	n.254C>G		non_coding_transcript_exon_variant	2/5	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

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

Feb 06, 2023

The c.2476C>G (p.L826V) alteration is located in exon 16 (coding exon 15) of the DENND2C gene. This alteration results from a C to G substitution at nucleotide position 2476, causing the leucine (L) at amino acid position 826 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	0.33
BayesDel_addAF	Benign	-0.065	T
BayesDel_noAF	Benign	-0.33
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Benign	0.011	.;T;T
Eigen	Pathogenic	0.83
Eigen_PC	Pathogenic	0.85
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.96	D;.;D
M_CAP	Benign	0.032	D
MetaRNN	Pathogenic	0.81	D;D;D
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.4	.;M;M
PrimateAI	Uncertain	0.75	T
PROVEAN	Uncertain	-2.7	D;D;.
REVEL	Benign	0.24
Sift	Uncertain	0.0080	D;D;.
Sift4G	Uncertain	0.010	D;D;D
Polyphen		0.93	P;D;D
Vest4		0.76
MutPred		0.49		.;Loss of catalytic residue at L883 (P = 0.0612);Loss of catalytic residue at L883 (P = 0.0612);
MVP		0.55
MPC		0.38
ClinPred		0.98	D
GERP RS		5.8
Varity_R		0.59
gMVP		0.29

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr1-115130358;