7-140527472-G-T

Position:

• chr7-140527472-G-T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_015689.5(DENND2A):​c.2351C>A​(p.Ala784Glu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: DENND2A NM_015689.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.30

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 Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.982

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DENND2A	NM_015689.5	c.2351C>A	p.Ala784Glu	missense_variant	15/20	ENST00000496613.6	NP_056504.3
DENND2A	NM_001318052.2	c.2351C>A	p.Ala784Glu	missense_variant	14/19		NP_001304981.1
DENND2A	NM_001362678.2	c.2351C>A	p.Ala784Glu	missense_variant	15/20		NP_001349607.1
DENND2A	NR_134477.1	n.2473-35C>A		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DENND2A	ENST00000496613.6	c.2351C>A	p.Ala784Glu	missense_variant	15/20	2	NM_015689.5	ENSP00000419654.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

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

Feb 28, 2024

The c.2351C>A (p.A784E) alteration is located in exon 13 (coding exon 13) of the DENND2A gene. This alteration results from a C to A substitution at nucleotide position 2351, causing the alanine (A) at amino acid position 784 to be replaced by a glutamic acid (E). 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	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.23	D
BayesDel_noAF	Uncertain	0.10
CADD	Pathogenic	29
DANN	Uncertain	0.99
DEOGEN2	Benign	0.31	T;T;T
Eigen	Uncertain	0.48
Eigen_PC	Uncertain	0.33
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Pathogenic	0.99	.;D;.
M_CAP	Uncertain	0.093	D
MetaRNN	Pathogenic	0.98	D;D;D
MetaSVM	Benign	-0.57	T
MutationAssessor	Pathogenic	3.5	H;H;H
PrimateAI	Uncertain	0.67	T
PROVEAN	Pathogenic	-4.5	D;D;D
REVEL	Uncertain	0.63
Sift	Pathogenic	0.0	D;D;D
Sift4G	Pathogenic	0.0010	D;D;D
Polyphen		0.99	D;D;D
Vest4		0.90
MutPred		0.90		Gain of ubiquitination at K780 (P = 0.0704);Gain of ubiquitination at K780 (P = 0.0704);Gain of ubiquitination at K780 (P = 0.0704);
MVP		0.68
MPC		0.79
ClinPred		1.0	D
GERP RS		4.0
Varity_R		0.95
gMVP		0.93

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr7-140227272;