NM_001330640.2:c.752C>G

Variant names:

• chr9-19290827-C-G
• rs756932382
• NM_001330640.2:c.752C>G

Variant summary

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

The NM_001330640.2(DENND4C):​c.752C>G​(p.Pro251Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,288 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. P251L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: DENND4C NM_001330640.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.91
• Publications: 0 publications found

Genes affected

DENND4C (HGNC:26079): (DENN domain containing 4C) Enables guanyl-nucleotide exchange factor activity. Predicted to be involved in cellular response to insulin stimulus; protein localization to plasma membrane; and regulation of Rab protein signal transduction. Located in Golgi apparatus and cytosol. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DENND4C	NM_001330640.2	c.752C>G	p.Pro251Arg	missense_variant	Exon 5 of 33	ENST00000434457.7	NP_001317569.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DENND4C	ENST00000434457.7	c.752C>G	p.Pro251Arg	missense_variant	Exon 5 of 33	5	NM_001330640.2	ENSP00000473469.1
DENND4C	ENST00000494124.2	n.68C>G		non_coding_transcript_exon_variant	Exon 1 of 28	1		ENSP00000473273.1
DENND4C	ENST00000602925.5	c.752C>G	p.Pro251Arg	missense_variant	Exon 5 of 32	5		ENSP00000473565.1
DENND4C	ENST00000380437.8	n.70C>G		non_coding_transcript_exon_variant	Exon 1 of 29	5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461288 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 726938

African (AFR) AF: 0.00 AC: 0 AN: 33466

American (AMR) AF: 0.00 AC: 0 AN: 44706

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26116

East Asian (EAS) AF: 0.00 AC: 0 AN: 39596

South Asian (SAS) AF: 0.00 AC: 0 AN: 86214

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53360

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1111702

Other (OTH) AF: 0.00 AC: 0 AN: 60364

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.52
BayesDel_addAF	Pathogenic	0.25	D
BayesDel_noAF	Uncertain	0.12
CADD	Pathogenic	27
DANN	Uncertain	1.0
Eigen	Pathogenic	0.88
Eigen_PC	Pathogenic	0.86
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.95	D;D
M_CAP	Benign	0.037	D
MetaRNN	Uncertain	0.69	D;D
MetaSVM	Uncertain	0.048	D
PhyloP100		7.9
PrimateAI	Uncertain	0.72	T
Sift4G	Uncertain	0.0060	D;D
Vest4		0.57
MVP		0.69
MPC		0.28
ClinPred		0.98	D
GERP RS		5.4
Varity_R		0.28
gMVP		0.65
Mutation Taster		=18/82	disease causing

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: rs756932382; hg19: chr9-19290825;