19-6467617-G-C

Variant names:

• chr19-6467617-G-C
• rs374565278
• NM_024898.4:c.2293C>G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_024898.4(DENND1C):​c.2293C>G​(p.Arg765Gly) variant causes a missense 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. 16/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R765W) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 31)
• Consequence: DENND1C NM_024898.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.01
• Publications: 0 publications found

Genes affected

DENND1C (HGNC:26225): (DENN domain containing 1C) The protein encoded by this gene functions as a guanine nucleotide exchange factor for the early endosomal small GTPase RAB35, which regulates endosomal membrane trafficking and is involved in actin polymerization. The encoded protein activates RAB35 by promoting the exchange of RAB35-bound GDP for GTP. This gene may play a role in linking RAB35 activation with the clathrin machinery. [provided by RefSeq, May 2017]

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.07036328).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_024898.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DENND1C	NM_024898.4	MANE Select	c.2293C>G	p.Arg765Gly	missense	Exon 23 of 23	NP_079174.2	Q8IV53-1
	DENND1C	NM_001290331.2		c.2161C>G	p.Arg721Gly	missense	Exon 21 of 21	NP_001277260.1	Q8IV53-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DENND1C	ENST00000381480.7	TSL:1 MANE Select	c.2293C>G	p.Arg765Gly	missense	Exon 23 of 23	ENSP00000370889.1	Q8IV53-1
	DENND1C	ENST00000590867.5	TSL:1	n.*1525C>G		non_coding_transcript_exon	Exon 21 of 21	ENSP00000465675.1	K7EKL5
	DENND1C	ENST00000590867.5	TSL:1	n.*1525C>G		3_prime_UTR	Exon 21 of 21	ENSP00000465675.1	K7EKL5

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 31

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.066
BayesDel_addAF	Benign	-0.34	T
BayesDel_noAF	Benign	-0.73
CADD	Benign	8.5
DANN	Benign	0.89
DEOGEN2	Benign	0.0013	T
Eigen	Benign	-0.93
Eigen_PC	Benign	-0.91
FATHMM_MKL	Benign	0.18	N
LIST_S2	Benign	0.27	T
M_CAP	Benign	0.0064	T
MetaRNN	Benign	0.070	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.0	N
PhyloP100		2.0
PrimateAI	Benign	0.26	T
PROVEAN	Benign	0.27	N
REVEL	Benign	0.092
Sift	Benign	0.36	T
Sift4G	Benign	0.38	T
Polyphen		0.0	B
Vest4		0.052
MutPred		0.11		Loss of glycosylation at P768 (P = 0.2311)
MVP		0.10
MPC		0.041
ClinPred		0.13	T
GERP RS		3.4
Varity_R		0.088
gMVP		0.083
Mutation Taster		=94/6	polymorphism

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

Other links and lift over

dbSNP: rs374565278; hg19: chr19-6467628;