Genetic Variant DENND2A:p.Val842Ile (chr7-140525774-C-T) – ACMG Classification: Likely_benign (-4 pts)

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_015689.5(DENND2A):c.2524G>A(p.Val842Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000741 in 1,605,172 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. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00011 ( 0 hom., cov: 31)

Exomes 𝑓: 0.000070 ( 0 hom. )

Consequence

DENND2A
NM_015689.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -4 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.03377974).

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>A	p.Val842Ile	missense	Exon 16 of 20	NP_056504.3	Q9ULE3-1
DENND2A	NM_001318052.2		c.2524G>A	p.Val842Ile	missense	Exon 15 of 19	NP_001304981.1	Q9ULE3-1
DENND2A	NM_001362678.2		c.2524G>A	p.Val842Ile	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>A	p.Val842Ile	missense	Exon 16 of 20	ENSP00000419654.1	Q9ULE3-1
DENND2A	ENST00000275884.10	TSL:1	c.2524G>A	p.Val842Ile	missense	Exon 15 of 19	ENSP00000275884.6	Q9ULE3-1
DENND2A	ENST00000537639.5	TSL:1	c.2524G>A	p.Val842Ile	missense	Exon 14 of 18	ENSP00000442245.1	Q9ULE3-1

Frequencies

GnomAD3 genomes

AF:

0.000112

AC:

AN:

152136

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000217

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

Gnomad ASJ

AF:

0.00173

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000154

AC:

AN:

240156

AF XY:

0.000122

show subpopulations

Gnomad AFR exome

AF:

0.000204

Gnomad AMR exome

AF:

0.000370

Gnomad ASJ exome

AF:

0.00122

Gnomad EAS exome

AF:

0.000173

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000909

Gnomad OTH exome

AF:

0.000692

GnomAD4 exome

AF:

0.0000702

AC:

102

AN:

1453036

Hom.:

Cov.:

AF XY:

0.0000581

AC XY:

AN XY:

722504

show subpopulations

African (AFR)

AF:

0.000543

AC:

AN:

33174

American (AMR)

AF:

0.000457

AC:

AN:

43734

Ashkenazi Jewish (ASJ)

AF:

0.00143

AC:

AN:

25964

East Asian (EAS)

AF:

0.000102

AC:

AN:

39142

South Asian (SAS)

AF:

0.0000119

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:

0.0000144

AC:

AN:

1107678

Other (OTH)

AF:

0.0000999

AC:

AN:

60046

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.471

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

AF:

0.000112

AC:

AN:

152136

Hom.:

Cov.:

AF XY:

0.000148

AC XY:

AN XY:

74316

show subpopulations

African (AFR)

AF:

0.000217

AC:

AN:

41410

American (AMR)

AF:

0.0000655

AC:

AN:

15276

Ashkenazi Jewish (ASJ)

AF:

0.00173

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5184

South Asian (SAS)

AF:

0.00

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10608

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

68044

Other (OTH)

AF:

0.00

AC:

AN:

2092

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.487

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome 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

Alfa

AF:

0.000140

Hom.:

Bravo

AF:

0.000276

ESP6500AA

AF:

0.000506

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000149

AC:

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.076

BayesDel_addAF

Benign

-0.52

BayesDel_noAF

Benign

-0.68

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.024

Eigen

Benign

-0.24

Eigen_PC

Benign

-0.084

FATHMM_MKL

Uncertain

0.89

LIST_S2

Benign

0.76

M_CAP

Benign

0.0031

MetaRNN

Benign

0.034

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.2

PhyloP100

3.6

PrimateAI

Benign

0.30

PROVEAN

Benign

-0.44

REVEL

Benign

0.041

Sift

Benign

0.31

Sift4G

Benign

0.19

Polyphen

0.0040

Vest4

0.24

MVP

0.093

MPC

0.15

ClinPred

0.016

GERP RS

4.4

Varity_R

0.050

gMVP

0.20

Mutation Taster

=91/9

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

Splicevardb

2.0

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over