NM_001256404.2:c.2406G>T

Variant names:

• chr1-114594498-C-A
• rs1230835423
• NM_001256404.2:c.2406G>T

Variant summary

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

The NM_001256404.2(DENND2C):​c.2406G>T​(p.Leu802Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000372 in 1,613,828 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: DENND2C NM_001256404.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.0260
• Publications: 0 publications found

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]

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=0.15050593).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001256404.2. 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
	DENND2C	NM_001256404.2	MANE Select	c.2406G>T	p.Leu802Phe	missense	Exon 18 of 21	NP_001243333.1	Q68D51-1
	DENND2C	NM_198459.4		c.2235G>T	p.Leu745Phe	missense	Exon 15 of 18	NP_940861.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DENND2C	ENST00000393274.6	TSL:5 MANE Select	c.2406G>T	p.Leu802Phe	missense	Exon 18 of 21	ENSP00000376955.1	Q68D51-1
	DENND2C	ENST00000481894.1	TSL:1	n.1990G>T		non_coding_transcript_exon	Exon 16 of 18
	DENND2C	ENST00000935533.1		c.2406G>T	p.Leu802Phe	missense	Exon 17 of 20	ENSP00000605592.1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152116 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000796 AC: 2 AN: 251374 AF XY: 0.0000147

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000326

GnomAD4 exome AF: 0.00000342 AC: 5 AN: 1461712 Hom.: 0 Cov.: 30 AF XY: 0.00000413 AC XY: 3 AN XY: 727146

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33472

American (AMR) AF: 0.0000224 AC: 1 AN: 44722

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 39674

South Asian (SAS) AF: 0.0000348 AC: 3 AN: 86242

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53356

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111960

Other (OTH) AF: 0.0000166 AC: 1 AN: 60390

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000874263), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152116 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74320

African (AFR) AF: 0.00 AC: 0 AN: 41416

American (AMR) AF: 0.00 AC: 0 AN: 15264

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5198

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10614

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68020

Other (OTH) AF: 0.00 AC: 0 AN: 2084

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

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	0.21
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Benign	-0.52
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Benign	0.014	T
Eigen	Benign	-0.26
Eigen_PC	Benign	-0.32
FATHMM_MKL	Benign	0.72	D
LIST_S2	Benign	0.66	T
M_CAP	Benign	0.011	T
MetaRNN	Benign	0.15	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.6	M
PhyloP100		0.026
PrimateAI	Uncertain	0.53	T
PROVEAN	Benign	-2.0	N
REVEL	Benign	0.061
Sift	Benign	0.11	T
Sift4G	Benign	0.72	T
Polyphen		0.56	P
Vest4		0.48
MutPred		0.29		Loss of helix (P = 0.079)
MVP		0.27
MPC		0.34
ClinPred		0.39	T
GERP RS		-0.40
Varity_R		0.075
gMVP		0.48
Mutation Taster		=83/17	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: rs1230835423; hg19: chr1-115137119;