7-140527428-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_015689.5(DENND2A):c.2395A>G(p.Ile799Val) variant causes a missense change. The variant allele was found at a frequency of 0.00000069 in 1,449,270 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: DENND2A NM_015689.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.73

Genes affected

DENND2A (HGNC:22212): (DENN domain containing 2A) Enables guanyl-nucleotide exchange factor activity. Involved in retrograde transport, endosome to Golgi. Located in actin cytoskeleton. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.37545955).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DENND2A	NM_015689.5	c.2395A>G	p.Ile799Val	missense_variant	15/20	ENST00000496613.6
DENND2A	NM_001318052.2	c.2395A>G	p.Ile799Val	missense_variant	14/19
DENND2A	NM_001362678.2	c.2395A>G	p.Ile799Val	missense_variant	15/20
DENND2A	NR_134477.1	n.2482A>G		non_coding_transcript_exon_variant	13/18

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DENND2A	ENST00000496613.6	c.2395A>G	p.Ile799Val	missense_variant	15/20	2	NM_015689.5	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.90e-7 AC: 1 AN: 1449270 Hom.: 0 Cov.: 30 AF XY: 0.00000139 AC XY: 1 AN XY: 719816

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000119

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 21, 2023

The c.2395A>G (p.I799V) alteration is located in exon 13 (coding exon 13) of the DENND2A gene. This alteration results from a A to G substitution at nucleotide position 2395, causing the isoleucine (I) at amino acid position 799 to be replaced by a valine (V). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.20
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Benign	-0.53
Cadd	Uncertain	24
Dann	Uncertain	1.0
DEOGEN2	Benign	0.058	T;T;T
Eigen	Uncertain	0.29
Eigen_PC	Uncertain	0.30
FATHMM_MKL	Uncertain	0.84	D
M_CAP	Benign	0.0062	T
MetaRNN	Benign	0.38	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.6	L;L;L
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.55	T
PROVEAN	Benign	-0.83	N;N;N
REVEL	Benign	0.10
Sift	Benign	0.076	T;T;T
Sift4G	Uncertain	0.056	T;T;T
Polyphen		0.73	P;P;P
Vest4		0.20
MutPred		0.68		Gain of catalytic residue at I799 (P = 0.0778);Gain of catalytic residue at I799 (P = 0.0778);Gain of catalytic residue at I799 (P = 0.0778);
MVP		0.043
MPC		0.18
ClinPred		0.85	D
GERP RS		3.7
Varity_R		0.15
gMVP		0.36

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr7-140227228;