1-114600351-G-A

Position:

• chr1-114600351-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001256404.2(DENND2C):​c.1958C>T​(p.Ser653Phe) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/23 in silico tools predict a benign outcome for this variant. 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: DENND2C NM_001256404.2 missense, splice_region
• Scores: Splicing: ADA: 0.06627
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.49

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.124833405).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DENND2C	NM_001256404.2	c.1958C>T	p.Ser653Phe	missense_variant, splice_region_variant	15/21	ENST00000393274.6	NP_001243333.1
DENND2C	NM_198459.4	c.1787C>T	p.Ser596Phe	missense_variant, splice_region_variant	12/18		NP_940861.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DENND2C	ENST00000393274.6	c.1958C>T	p.Ser653Phe	missense_variant, splice_region_variant	15/21	5	NM_001256404.2	ENSP00000376955.1
DENND2C	ENST00000481894.1	n.1246C>T		splice_region_variant, non_coding_transcript_exon_variant	12/18	1
DENND2C	ENST00000393276.7	c.1787C>T	p.Ser596Phe	missense_variant, splice_region_variant	12/18	5		ENSP00000376957.3

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

Jul 10, 2023

The c.1787C>T (p.S596F) alteration is located in exon 12 (coding exon 11) of the DENND2C gene. This alteration results from a C to T substitution at nucleotide position 1787, causing the serine (S) at amino acid position 596 to be replaced by a phenylalanine (F). 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	0.16
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Benign	-0.47
CADD	Benign	23
DANN	Uncertain	0.98
DEOGEN2	Benign	0.0054	.;T;T
Eigen	Benign	-0.11
Eigen_PC	Benign	0.078
FATHMM_MKL	Uncertain	0.81	D
LIST_S2	Benign	0.86	D;.;D
M_CAP	Benign	0.023	T
MetaRNN	Benign	0.12	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.69	.;N;N
PrimateAI	Uncertain	0.50	T
PROVEAN	Benign	-0.27	N;N;.
REVEL	Benign	0.13
Sift	Benign	0.22	T;T;.
Sift4G	Benign	0.12	T;T;T
Polyphen		0.0060	B;B;B
Vest4		0.39
MutPred		0.48		.;Loss of disorder (P = 0.0143);Loss of disorder (P = 0.0143);
MVP		0.33
MPC		0.19
ClinPred		0.75	D
GERP RS		5.0
Varity_R		0.091
gMVP		0.44

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.066
dbscSNV1_RF	Benign	0.27
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: chr1-115142972; COSMIC: COSV67920085;