9-19296096-C-G

Variant names:

• chr9-19296096-C-G
• rs750723437
• NM_001330640.2:c.890C>G

Variant summary

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

The NM_001330640.2(DENND4C):​c.890C>G​(p.Pro297Arg) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,826 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 11/19 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. P297H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: DENND4C NM_001330640.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.71
• 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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.21412805).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DENND4C	NM_001330640.2	c.890C>G	p.Pro297Arg	missense_variant	Exon 6 of 33	ENST00000434457.7	NP_001317569.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DENND4C	ENST00000434457.7	c.890C>G	p.Pro297Arg	missense_variant	Exon 6 of 33	5	NM_001330640.2	ENSP00000473469.1
DENND4C	ENST00000494124.2	n.206C>G		non_coding_transcript_exon_variant	Exon 2 of 28	1		ENSP00000473273.1
DENND4C	ENST00000602925.5	c.890C>G	p.Pro297Arg	missense_variant	Exon 6 of 32	5		ENSP00000473565.1
DENND4C	ENST00000380437.8	n.208C>G		non_coding_transcript_exon_variant	Exon 2 of 29	5

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461826 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 727224

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39688

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53416

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111970

Other (OTH) AF: 0.00 AC: 0 AN: 60390

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Benign	-0.49
CADD	Benign	23
DANN	Benign	0.94
Eigen	Benign	-0.014
Eigen_PC	Benign	0.026
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.86	D;D
M_CAP	Benign	0.016	T
MetaRNN	Benign	0.21	T;T
MetaSVM	Benign	-1.0	T
PhyloP100		5.7
PrimateAI	Uncertain	0.54	T
Sift4G	Benign	0.49	T;T
Vest4		0.41
MVP		0.29
MPC		0.12
ClinPred		0.72	D
GERP RS		3.8
Varity_R		0.040
gMVP		0.53
Mutation Taster		=93/7	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: rs750723437; hg19: chr9-19296094;