rs138727736

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.1120A>G(p.Thr374Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00549 in 1,612,002 control chromosomes in the GnomAD database, including 48 homozygotes. 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 Likely benign (★★).

Frequency

Genomes: 𝑓 0.0037 ( 1 hom., cov: 32)

Exomes 𝑓: 0.0057 ( 47 hom. )

Consequence

CD2AP
NM_012120.3 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: -1.21

Publications

16 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: AD, AR Classification: STRONG, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics
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=0.0028515756).

BP6

Variant 6-47595872-A-G is Benign according to our data. Variant chr6-47595872-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 260180.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.00365 (556/152186) while in subpopulation SAS AF = 0.0127 (61/4818). AF 95% confidence interval is 0.0101. There are 1 homozygotes in GnomAd4. There are 251 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAdExome4 at 47 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CD2AP	NM_012120.3 link	c.1120A>G	p.Thr374Ala	missense_variant	Exon 12 of 18	ENST00000359314.5	NP_036252.1	Q9Y5K6
CD2AP	XM_005248976.2 link	c.1108A>G	p.Thr370Ala	missense_variant	Exon 12 of 18		XP_005249033.1
CD2AP	XM_011514449.3 link	c.973A>G	p.Thr325Ala	missense_variant	Exon 11 of 17		XP_011512751.1
CD2AP	XM_017010641.2 link	c.1120A>G	p.Thr374Ala	missense_variant	Exon 12 of 14		XP_016866130.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CD2AP	ENST00000359314.5 link	c.1120A>G	p.Thr374Ala	missense_variant	Exon 12 of 18	1	NM_012120.3	ENSP00000352264.5		Q9Y5K6

Frequencies

GnomAD3 genomes

AF:

0.00368

AC:

559

AN:

152068

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00101

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00393

Gnomad ASJ

AF:

0.00259

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.0127

Gnomad FIN

AF:

0.000659

Gnomad MID

AF:

0.0158

Gnomad NFE

AF:

0.00538

Gnomad OTH

AF:

0.00384

GnomAD2 exomes

AF:

0.00508

AC:

1274

AN:

250646

AF XY:

0.00587

show subpopulations

Gnomad AFR exome

AF:

0.000927

Gnomad AMR exome

AF:

0.00369

Gnomad ASJ exome

AF:

0.00428

Gnomad EAS exome

AF:

0.000109

Gnomad FIN exome

AF:

0.000509

Gnomad NFE exome

AF:

0.00515

Gnomad OTH exome

AF:

0.00818

GnomAD4 exome

AF:

0.00568

AC:

8290

AN:

1459816

Hom.:

Cov.:

AF XY:

0.00606

AC XY:

4405

AN XY:

726322

show subpopulations

African (AFR)

AF:

0.00105

AC:

AN:

33382

American (AMR)

AF:

0.00338

AC:

151

AN:

44636

Ashkenazi Jewish (ASJ)

AF:

0.00376

AC:

AN:

26052

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39658

South Asian (SAS)

AF:

0.0162

AC:

1399

AN:

86106

European-Finnish (FIN)

AF:

0.000768

AC:

AN:

53400

Middle Eastern (MID)

AF:

0.0235

AC:

135

AN:

5750

European-Non Finnish (NFE)

AF:

0.00544

AC:

6044

AN:

1110532

Other (OTH)

AF:

0.00640

AC:

386

AN:

60300

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.465

Heterozygous variant carriers

360

720

1079

1439

1799

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.00365

AC:

556

AN:

152186

Hom.:

Cov.:

AF XY:

0.00337

AC XY:

251

AN XY:

74426

show subpopulations

African (AFR)

AF:

0.000987

AC:

AN:

41548

American (AMR)

AF:

0.00393

AC:

AN:

15274

Ashkenazi Jewish (ASJ)

AF:

0.00259

AC:

AN:

3470

East Asian (EAS)

AF:

0.000193

AC:

AN:

5172

South Asian (SAS)

AF:

0.0127

AC:

AN:

4818

European-Finnish (FIN)

AF:

0.000659

AC:

AN:

10618

Middle Eastern (MID)

AF:

0.0136

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00537

AC:

365

AN:

67972

Other (OTH)

AF:

0.00380

AC:

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

109

136

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00520

Hom.:

Bravo

AF:

0.00349

TwinsUK

AF:

0.00485

AC:

ALSPAC

AF:

0.00467

AC:

ESP6500AA

AF:

0.000454

AC:

ESP6500EA

AF:

0.00535

AC:

ExAC

AF:

0.00502

AC:

609

Asia WGS

AF:

0.00549

AC:

AN:

3478

EpiCase

AF:

0.00694

EpiControl

AF:

0.00616

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:4

Sep 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

CD2AP: BP4, BS1, BS2 -

Sep 13, 2020

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 19131354, 27884173, 26997877) -

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Jan 06, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Focal segmental glomerulosclerosis 3, susceptibility to

Benign:1

Mar 06, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

not specified

Benign:1

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Focal segmental glomerulosclerosis

Benign:1

Sep 28, 2022

Genome Diagnostics Laboratory, The Hospital for Sick Children

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.059

BayesDel_addAF

Benign

-0.73

BayesDel_noAF

Benign

-0.81

CADD

Benign

0.081

(source)

DANN

Benign

0.40

DEOGEN2

Benign

0.12

Eigen

Benign

-1.5

Eigen_PC

Benign

-1.5

FATHMM_MKL

Benign

0.013

LIST_S2

Benign

0.41

MetaRNN

Benign

0.0029

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.49

PhyloP100

-1.2

PrimateAI

Benign

0.25

PROVEAN

Benign

0.47

REVEL

Benign

0.064

Sift

Benign

0.73

Sift4G

Benign

0.77

Polyphen

0.0

Vest4

0.022

MVP

0.25

MPC

0.070

ClinPred

0.00027

GERP RS

-5.2

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.016

gMVP

0.099

Mutation Taster

=99/1

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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rs138727736

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over