Genetic Variant DENND2A:p.Val842Leu (chr7-140525774-C-G) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2BP4

The NM_015689.5(DENND2A):c.2524G>C(p.Val842Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000688 in 1,453,040 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V842I) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 31)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

DENND2A
NM_015689.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 3.57

Publications

0 publications found

Variant links:

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]

DENND2A links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.29865283).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_015689.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
DENND2A	NM_015689.5	MANE Select	c.2524G>C	p.Val842Leu	missense	Exon 16 of 20	NP_056504.3	Q9ULE3-1
DENND2A	NM_001318052.2		c.2524G>C	p.Val842Leu	missense	Exon 15 of 19	NP_001304981.1	Q9ULE3-1
DENND2A	NM_001362678.2		c.2524G>C	p.Val842Leu	missense	Exon 16 of 20	NP_001349607.1	Q9ULE3-1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
DENND2A	ENST00000496613.6	TSL:2 MANE Select	c.2524G>C	p.Val842Leu	missense	Exon 16 of 20	ENSP00000419654.1	Q9ULE3-1
DENND2A	ENST00000275884.10	TSL:1	c.2524G>C	p.Val842Leu	missense	Exon 15 of 19	ENSP00000275884.6	Q9ULE3-1
DENND2A	ENST00000537639.5	TSL:1	c.2524G>C	p.Val842Leu	missense	Exon 14 of 18	ENSP00000442245.1	Q9ULE3-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.88e-7

AC:

AN:

1453040

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

722506

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33174

American (AMR)

AF:

0.00

AC:

AN:

43734

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25966

East Asian (EAS)

AF:

0.00

AC:

AN:

39142

South Asian (SAS)

AF:

0.00

AC:

AN:

84344

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53212

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5742

European-Non Finnish (NFE)

AF:

9.03e-7

AC:

AN:

1107680

Other (OTH)

AF:

0.00

AC:

AN:

60046

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Benign

-0.22

BayesDel_noAF

Benign

-0.56

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.025

Eigen

Benign

-0.25

Eigen_PC

Benign

-0.087

FATHMM_MKL

Uncertain

0.93

LIST_S2

Uncertain

0.94

M_CAP

Benign

0.0037

MetaRNN

Benign

0.30

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.90

PhyloP100

3.6

PrimateAI

Benign

0.36

PROVEAN

Benign

-1.2

REVEL

Benign

0.033

Sift

Benign

0.34

Sift4G

Benign

0.27

Polyphen

0.0030

Vest4

0.46

MutPred

0.76

Gain of loop (P = 0.1069)

MVP

0.11

MPC

0.25

ClinPred

0.70

GERP RS

4.4

Varity_R

0.10

gMVP

0.32

Mutation Taster

=92/8

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over