7-140544632-A-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_015689.5(DENND2A):c.2313T>G(p.Ile771Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I771T) has been classified 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: -2.47

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.2017684).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DENND2A	NM_015689.5	c.2313T>G	p.Ile771Met	missense_variant	14/20	ENST00000496613.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DENND2A	ENST00000496613.6	c.2313T>G	p.Ile771Met	missense_variant	14/20	2	NM_015689.5	P1

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

Dec 19, 2022

The c.2313T>G (p.I771M) alteration is located in exon 12 (coding exon 12) of the DENND2A gene. This alteration results from a T to G substitution at nucleotide position 2313, causing the isoleucine (I) at amino acid position 771 to be replaced by a methionine (M). 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	0.11
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Benign	-0.49
Cadd	Benign	3.5
Dann	Benign	0.96
DEOGEN2	Benign	0.036	T;T;T;.;.
Eigen	Benign	-1.0
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.16	N
M_CAP	Benign	0.0053	T
MetaRNN	Benign	0.20	T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.4	L;L;L;.;L
MutationTaster	Benign	0.98	N;N;N;N
PrimateAI	Benign	0.42	T
PROVEAN	Benign	-1.9	N;N;N;N;N
REVEL	Benign	0.16
Sift	Uncertain	0.029	D;D;D;D;D
Sift4G	Uncertain	0.049	D;D;D;.;T
Polyphen		0.014	B;B;B;.;P
Vest4		0.47
MutPred		0.58		Loss of ubiquitination at K774 (P = 0.064);Loss of ubiquitination at K774 (P = 0.064);Loss of ubiquitination at K774 (P = 0.064);.;Loss of ubiquitination at K774 (P = 0.064);
MVP		0.20
MPC		0.25
ClinPred		0.83	D
GERP RS		-5.0
Varity_R		0.23
gMVP		0.44

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: chr7-140244432;