Variant chr1-114600876-G-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_001256404.2(DENND2C):c.1900C>T(p.Pro634Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,461,810 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: 0.0000027 ( 0 hom. )

Consequence

DENND2C
NM_001256404.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 10.0

Variant links:

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 links:

DENND2C (HGNC:):

DENND2C links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.931

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DENND2C	NM_001256404.2 linkuse as main transcript	c.1900C>T	p.Pro634Ser	missense_variant	14/21	ENST00000393274.6	NP_001243333.1	Q68D51-1
DENND2C	NM_198459.4 linkuse as main transcript	c.1729C>T	p.Pro577Ser	missense_variant	11/18		NP_940861.3	Q68D51-3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
DENND2C	ENST00000393274.6 linkuse as main transcript	c.1900C>T	p.Pro634Ser	missense_variant	14/21	5	NM_001256404.2	ENSP00000376955.1	Q68D51-1
DENND2C	ENST00000481894.1 linkuse as main transcript	n.1188C>T		non_coding_transcript_exon_variant	11/18	1
DENND2C	ENST00000393276.7 linkuse as main transcript	c.1729C>T	p.Pro577Ser	missense_variant	11/18	5		ENSP00000376957.3	Q68D51-3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000274

AC:

AN:

1461810

Hom.:

Cov.:

AF XY:

0.00000550

AC XY:

AN XY:

727202

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

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.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 05, 2022

The c.1729C>T (p.P577S) alteration is located in exon 11 (coding exon 10) of the DENND2C gene. This alteration results from a C to T substitution at nucleotide position 1729, causing the proline (P) at amino acid position 577 to be replaced by a serine (S). 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

0.99

BayesDel_addAF

Pathogenic

0.39

BayesDel_noAF

Pathogenic

0.32

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.14

.;T;T

Eigen

Pathogenic

1.1

Eigen_PC

Pathogenic

0.99

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

1.0

D;.;D

M_CAP

Uncertain

0.088

MetaRNN

Pathogenic

0.93

D;D;D

MetaSVM

Uncertain

0.57

MutationAssessor

Pathogenic

3.4

.;M;M

PrimateAI

Uncertain

0.78

PROVEAN

Pathogenic

-7.8

D;D;D

REVEL

Pathogenic

0.78

Sift

Pathogenic

0.0

D;D;D

Sift4G

Pathogenic

0.0

D;D;D

Polyphen

1.0

D;D;D

Vest4

0.88

MutPred

0.80

.;Loss of sheet (P = 0.0817);Loss of sheet (P = 0.0817);

MVP

0.90

MPC

0.38

ClinPred

1.0

GERP RS

5.2

Varity_R

0.87

gMVP

0.90

Splicing

Name

Calibrated prediction

Score

Prediction

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over