chr1-114587769-T-G

Variant names:

• chr1-114587769-T-G
• rs1257585310
• NM_001256404.2:c.2615A>C

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_001256404.2(DENND2C):​c.2615A>C​(p.Gln872Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000342 in 1,461,856 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: not found (cov: 32)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: DENND2C NM_001256404.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.67

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]

LOC105378914 (HGNC:):

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.98

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DENND2C	NM_001256404.2	c.2615A>C	p.Gln872Pro	missense_variant	Exon 19 of 21	ENST00000393274.6	NP_001243333.1
DENND2C	NM_198459.4	c.2444A>C	p.Gln815Pro	missense_variant	Exon 16 of 18		NP_940861.3
LOC105378914	XR_947719.4	n.*150T>G		downstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DENND2C	ENST00000393274.6	c.2615A>C	p.Gln872Pro	missense_variant	Exon 19 of 21	5	NM_001256404.2	ENSP00000376955.1
DENND2C	ENST00000481894.1	n.2199A>C		non_coding_transcript_exon_variant	Exon 17 of 18	1
DENND2C	ENST00000393276.7	c.2444A>C	p.Gln815Pro	missense_variant	Exon 16 of 18	5		ENSP00000376957.3
DENND2C	ENST00000495031.5	n.222A>C		non_coding_transcript_exon_variant	Exon 2 of 5	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251376 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135854

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000879

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000342 AC: 5 AN: 1461856 Hom.: 0 Cov.: 31 AF XY: 0.00000550 AC XY: 4 AN XY: 727232

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000360

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jan 29, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.2444A>C (p.Q815P) alteration is located in exon 16 (coding exon 15) of the DENND2C gene. This alteration results from a A to C substitution at nucleotide position 2444, causing the glutamine (Q) at amino acid position 815 to be replaced by a proline (P). 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	0.89
BayesDel_addAF	Pathogenic	0.34	D
BayesDel_noAF	Pathogenic	0.25
CADD	Pathogenic	30
DANN	Uncertain	0.99
DEOGEN2	Benign	0.26	.;T;T
Eigen	Pathogenic	0.88
Eigen_PC	Pathogenic	0.84
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	D;.;D
M_CAP	Uncertain	0.11	D
MetaRNN	Pathogenic	0.98	D;D;D
MetaSVM	Uncertain	-0.072	T
MutationAssessor	Pathogenic	3.0	.;M;M
PrimateAI	Pathogenic	0.83	D
PROVEAN	Pathogenic	-5.3	D;D;.
REVEL	Pathogenic	0.79
Sift	Pathogenic	0.0	D;D;.
Sift4G	Uncertain	0.0020	D;D;D
Polyphen		1.0	D;D;D
Vest4		0.99
MutPred		0.91		.;Gain of catalytic residue at Q872 (P = 0.2026);Gain of catalytic residue at Q872 (P = 0.2026);
MVP		0.91
MPC		0.41
ClinPred		0.99	D
GERP RS		5.9
Varity_R		0.91
gMVP		0.90

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs1257585310; hg19: chr1-115130390;