7-140527331-A-G

Position:

• chr7-140527331-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_015689.5(DENND2A):​c.2492T>C​(p.Leu831Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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: 8.67

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 2 ACMG points.

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DENND2A	NM_015689.5	c.2492T>C	p.Leu831Pro	missense_variant	15/20	ENST00000496613.6	NP_056504.3
DENND2A	NM_001318052.2	c.2492T>C	p.Leu831Pro	missense_variant	14/19		NP_001304981.1
DENND2A	NM_001362678.2	c.2492T>C	p.Leu831Pro	missense_variant	15/20		NP_001349607.1
DENND2A	NR_134477.1	n.2579T>C		non_coding_transcript_exon_variant	13/18

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DENND2A	ENST00000496613.6	c.2492T>C	p.Leu831Pro	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

Sep 26, 2023

The c.2492T>C (p.L831P) alteration is located in exon 13 (coding exon 13) of the DENND2A gene. This alteration results from a T to C substitution at nucleotide position 2492, causing the leucine (L) at amino acid position 831 to be replaced by a proline (P). 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	0.98
BayesDel_addAF	Uncertain	0.072	D
BayesDel_noAF	Benign	-0.090
CADD	Pathogenic	28
DANN	Uncertain	1.0
Eigen	Uncertain	0.68
Eigen_PC	Uncertain	0.58
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.18	T
M_CAP	Uncertain	0.12	D
MetaRNN	Uncertain	0.46	T
MetaSVM	Benign	-0.99	T
PROVEAN	Benign	-1.2	N
REVEL	Benign	0.26
Sift	Pathogenic	0.0	D
MutPred		0.14		Gain of methylation at K162 (P = 0.0371);
MVP		0.50
ClinPred		1.0	D
GERP RS		5.0

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: chr7-140227131;