rs201488135

Variant names:

• chr19-6467632-C-T
• rs201488135
• NM_024898.4:c.2278G>A

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_024898.4(DENND1C):​c.2278G>A​(p.Ala760Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000767 in 1,551,158 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000085 (1 hom., cov: 31)
  • Exomes 𝑓: 0.000076 (1 hom.)
• Consequence: DENND1C NM_024898.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.811
• Publications: 4 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: Likely_benign. The variant received -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.073097736).

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.2278G>A	p.Ala760Thr	missense	Exon 23 of 23	NP_079174.2	Q8IV53-1
	DENND1C	NM_001290331.2		c.2146G>A	p.Ala716Thr	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.2278G>A	p.Ala760Thr	missense	Exon 23 of 23	ENSP00000370889.1	Q8IV53-1
	DENND1C	ENST00000590867.5	TSL:1	n.*1510G>A		non_coding_transcript_exon	Exon 21 of 21	ENSP00000465675.1	K7EKL5
	DENND1C	ENST00000590867.5	TSL:1	n.*1510G>A		3_prime_UTR	Exon 21 of 21	ENSP00000465675.1	K7EKL5

Frequencies

GnomAD3 genomes AF: 0.0000855 AC: 13 AN: 152104 Hom.: 1 Cov.: 31

Gnomad AFR AF: 0.0000242

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000656

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.000621

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.0000735

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000524 AC: 10 AN: 191014 AF XY: 0.0000879

Gnomad AFR exome AF: 0.0000696

Gnomad AMR exome AF: 0.0000859

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000653

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000547

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000758 AC: 106 AN: 1398936 Hom.: 1 Cov.: 31 AF XY: 0.0000709 AC XY: 49 AN XY: 691062

African (AFR) AF: 0.0000974 AC: 3 AN: 30798

American (AMR) AF: 0.0000613 AC: 2 AN: 32624

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 22108

East Asian (EAS) AF: 0.0000258 AC: 1 AN: 38822

South Asian (SAS) AF: 0.0000662 AC: 5 AN: 75484

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51510

Middle Eastern (MID) AF: 0.00460 AC: 25 AN: 5440

European-Non Finnish (NFE) AF: 0.0000572 AC: 62 AN: 1084610

Other (OTH) AF: 0.000139 AC: 8 AN: 57540

GnomAD4 genome AF: 0.0000854 AC: 13 AN: 152222 Hom.: 1 Cov.: 31 AF XY: 0.000108 AC XY: 8 AN XY: 74414

African (AFR) AF: 0.0000241 AC: 1 AN: 41520

American (AMR) AF: 0.0000655 AC: 1 AN: 15262

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5184

South Asian (SAS) AF: 0.000622 AC: 3 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10610

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.0000735 AC: 5 AN: 68032

Other (OTH) AF: 0.00 AC: 0 AN: 2114

Alfa AF: 0.0000441 Hom.: 0

Bravo AF: 0.0000604

ESP6500AA AF: 0.000527 AC: 2

ESP6500EA AF: 0.000121 AC: 1

ExAC AF: 0.0000497 AC: 6

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.071
BayesDel_addAF	Benign	-0.51	T
BayesDel_noAF	Benign	-0.78
CADD	Benign	1.3
DANN	Benign	0.91
DEOGEN2	Benign	0.0016	T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.032	N
LIST_S2	Benign	0.50	T
M_CAP	Benign	0.010	T
MetaRNN	Benign	0.073	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.34	N
PhyloP100		-0.81
PrimateAI	Benign	0.29	T
PROVEAN	Benign	-0.35	N
REVEL	Benign	0.038
Sift	Benign	0.17	T
Sift4G	Benign	0.30	T
Polyphen		0.059	B
Vest4		0.057
MVP		0.040
MPC		0.035
ClinPred		0.058	T
GERP RS		2.0
Varity_R		0.024
gMVP		0.10
Mutation Taster		=95/5	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: rs201488135; hg19: chr19-6467643; COSMIC: COSV57569152; COSMIC: COSV57569152;