rs34069459

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_012120.3(CD2AP):c.1743T>A(p.Asn581Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00197 in 1,613,206 control chromosomes in the GnomAD database, including 53 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.011 ( 26 hom., cov: 32)

Exomes 𝑓: 0.0010 ( 27 hom. )

Consequence

CD2AP
NM_012120.3 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: 0.492

Publications

3 publications found

Variant links:

Genes affected

CD2AP (HGNC:14258): (CD2 associated protein) This gene encodes a scaffolding molecule that regulates the actin cytoskeleton. The protein directly interacts with filamentous actin and a variety of cell membrane proteins through multiple actin binding sites, SH3 domains, and a proline-rich region containing binding sites for SH3 domains. The cytoplasmic protein localizes to membrane ruffles, lipid rafts, and the leading edges of cells. It is implicated in dynamic actin remodeling and membrane trafficking that occurs during receptor endocytosis and cytokinesis. Haploinsufficiency of this gene is implicated in susceptibility to glomerular disease. [provided by RefSeq, Jul 2008]

CD2AP Gene-Disease associations (from GenCC):

focal segmental glomerulosclerosis 3, susceptibility to
Inheritance: AR, AD Classification: DEFINITIVE, STRONG, LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), ClinGen
inherited focal segmental glomerulosclerosis
Inheritance: AD Classification: MODERATE Submitted by: ClinGen
familial idiopathic steroid-resistant nephrotic syndrome
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

CD2AP links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0021980107).

BP6

Variant 6-47609233-T-A is Benign according to our data. Variant chr6-47609233-T-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 260187.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0108 (1644/152068) while in subpopulation AFR AF = 0.037 (1535/41514). AF 95% confidence interval is 0.0354. There are 26 homozygotes in GnomAd4. There are 740 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 26 AD,AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_012120.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CD2AP	NM_012120.3	MANE Select	c.1743T>A	p.Asn581Lys	missense	Exon 16 of 18	NP_036252.1	Q9Y5K6

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CD2AP	ENST00000359314.5	TSL:1 MANE Select	c.1743T>A	p.Asn581Lys	missense	Exon 16 of 18	ENSP00000352264.5	Q9Y5K6
CD2AP	ENST00000865253.1		c.1746T>A	p.Asn582Lys	missense	Exon 16 of 18	ENSP00000535312.1
CD2AP	ENST00000931707.1		c.1734T>A	p.Asn578Lys	missense	Exon 16 of 18	ENSP00000601766.1

Frequencies

GnomAD3 genomes

AF:

0.0108

AC:

1642

AN:

151950

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0370

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00538

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000208

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000103

Gnomad OTH

AF:

0.00914

GnomAD2 exomes

AF:

0.00289

AC:

726

AN:

251038

AF XY:

0.00210

show subpopulations

Gnomad AFR exome

AF:

0.0383

Gnomad AMR exome

AF:

0.00229

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000882

Gnomad OTH exome

AF:

0.00196

GnomAD4 exome

AF:

0.00105

AC:

1530

AN:

1461138

Hom.:

Cov.:

AF XY:

0.000867

AC XY:

630

AN XY:

726920

show subpopulations

African (AFR)

AF:

0.0369

AC:

1234

AN:

33452

American (AMR)

AF:

0.00239

AC:

107

AN:

44714

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26122

East Asian (EAS)

AF:

0.00

AC:

AN:

39678

South Asian (SAS)

AF:

0.000139

AC:

AN:

86232

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53414

Middle Eastern (MID)

AF:

0.000529

AC:

AN:

5676

European-Non Finnish (NFE)

AF:

0.0000225

AC:

AN:

1111476

Other (OTH)

AF:

0.00247

AC:

149

AN:

60374

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.472

Heterozygous variant carriers

155

232

310

387

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

108

144

180

<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:

0.0108

AC:

1644

AN:

152068

Hom.:

Cov.:

AF XY:

0.00996

AC XY:

740

AN XY:

74294

show subpopulations

African (AFR)

AF:

0.0370

AC:

1535

AN:

41514

American (AMR)

AF:

0.00537

AC:

AN:

15264

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3466

East Asian (EAS)

AF:

0.00

AC:

AN:

5184

South Asian (SAS)

AF:

0.000208

AC:

AN:

4808

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10540

Middle Eastern (MID)

AF:

0.00

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.000103

AC:

AN:

67988

Other (OTH)

AF:

0.00905

AC:

AN:

2100

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

147

220

294

367

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<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:

0.00164

Hom.:

Bravo

AF:

0.0124

ESP6500AA

AF:

0.0363

AC:

160

ESP6500EA

AF:

0.000233

AC:

ExAC

AF:

0.00345

AC:

419

Asia WGS

AF:

0.00202

AC:

AN:

3478

EpiCase

AF:

0.0000545

EpiControl

AF:

0.000178

ClinVar

ClinVar submissions

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (3)

Kidney disorder (1)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.65

BayesDel_noAF

Benign

-0.67

CADD

Benign

(source)

DANN

Benign

0.97

DEOGEN2

Benign

0.23

Eigen

Benign

-0.76

Eigen_PC

Benign

-0.70

FATHMM_MKL

Benign

0.12

LIST_S2

Benign

0.65

MetaRNN

Benign

0.0022

MetaSVM

Benign

-1.0

MutationAssessor

Uncertain

2.3

PhyloP100

0.49

PrimateAI

Benign

0.33

PROVEAN

Benign

-0.48

REVEL

Benign

0.038

Sift

Benign

0.11

Sift4G

Benign

0.29

Polyphen

0.13

Vest4

0.24

MutPred

0.18

Gain of ubiquitination at N581 (P = 0.0211)

MVP

0.54

MPC

0.091

ClinPred

0.0034

GERP RS

1.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.047

gMVP

0.031

Mutation Taster

=97/3

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over