6-47577102-A-T

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BS1_SupportingBS2

The NM_012120.3(CD2AP):c.902A>T(p.Lys301Met) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.00019 in 1,465,330 control chromosomes in the GnomAD database, including 5 homozygotes. 2/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.00014 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00020 ( 5 hom. )

Consequence

CD2AP
NM_012120.3 missense, splice_region

Scores

Splicing: ADA: 0.9879

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:5

Conservation

PhyloP100: 7.14

Publications

8 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: Likely_benign. The variant received -5 ACMG points.

BS1

Variant frequency is greater than expected in population mid. GnomAdExome4 allele frequency = 0.000196 (257/1313068) while in subpopulation MID AF = 0.0172 (94/5474). AF 95% confidence interval is 0.0144. There are 5 homozygotes in GnomAdExome4. There are 139 alleles in the male GnomAdExome4 subpopulation. Median coverage is 21. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

BS2

High Homozygotes in GnomAdExome4 at 5 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
CD2AP	NM_012120.3 link	c.902A>T	p.Lys301Met	missense_variant, splice_region_variant	Exon 8 of 18	ENST00000359314.5	NP_036252.1
CD2AP	XM_005248976.2 link	c.890A>T	p.Lys297Met	missense_variant, splice_region_variant	Exon 8 of 18		XP_005249033.1
CD2AP	XM_011514449.3 link	c.755A>T	p.Lys252Met	missense_variant, splice_region_variant	Exon 7 of 17		XP_011512751.1
CD2AP	XM_017010641.2 link	c.902A>T	p.Lys301Met	missense_variant, splice_region_variant	Exon 8 of 14		XP_016866130.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CD2AP	ENST00000359314.5 link	c.902A>T	p.Lys301Met	missense_variant, splice_region_variant	Exon 8 of 18	1	NM_012120.3	ENSP00000352264.5
CD2AP	ENST00000463175.1 link	n.184A>T		splice_region_variant, non_coding_transcript_exon_variant	Exon 2 of 3	2

Frequencies

GnomAD3 genomes

AF:

0.000151

AC:

AN:

152144

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000724

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

Gnomad ASJ

AF:

0.000576

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.0287

Gnomad NFE

AF:

0.0000588

Gnomad OTH

AF:

0.00191

GnomAD2 exomes

AF:

0.000191

AC:

AN:

250902

AF XY:

0.000258

show subpopulations

Gnomad AFR exome

AF:

0.000186

Gnomad AMR exome

AF:

0.0000869

Gnomad ASJ exome

AF:

0.00179

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000185

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000196

AC:

257

AN:

1313068

Hom.:

Cov.:

AF XY:

0.000210

AC XY:

139

AN XY:

661250

show subpopulations

African (AFR)

AF:

0.000458

AC:

AN:

30560

American (AMR)

AF:

0.0000674

AC:

AN:

44498

Ashkenazi Jewish (ASJ)

AF:

0.00131

AC:

AN:

25096

East Asian (EAS)

AF:

0.00

AC:

AN:

38820

South Asian (SAS)

AF:

0.0000846

AC:

AN:

82728

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53308

Middle Eastern (MID)

AF:

0.0172

AC:

AN:

5474

European-Non Finnish (NFE)

AF:

0.0000870

AC:

AN:

977196

Other (OTH)

AF:

0.000379

AC:

AN:

55388

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.456

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

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:

0.000144

AC:

AN:

152262

Hom.:

Cov.:

AF XY:

0.000175

AC XY:

AN XY:

74444

show subpopulations

African (AFR)

AF:

0.0000722

AC:

AN:

41574

American (AMR)

AF:

0.0000654

AC:

AN:

15296

Ashkenazi Jewish (ASJ)

AF:

0.000576

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5178

South Asian (SAS)

AF:

0.00

AC:

AN:

4816

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10610

Middle Eastern (MID)

AF:

0.0274

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.0000588

AC:

AN:

68000

Other (OTH)

AF:

0.00189

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.495

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:

0.000268

Hom.:

Bravo

AF:

0.0000907

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000349

AC:

ExAC

AF:

0.000214

AC:

Asia WGS

AF:

0.000578

AC:

AN:

3474

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Focal segmental glomerulosclerosis 3, susceptibility to

Uncertain:2

Mar 23, 2020

Revvity Omics, Revvity

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Dec 24, 2019

Baylor Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. -

not provided

Uncertain:2

Nov 15, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces lysine, which is basic and polar, with methionine, which is neutral and non-polar, at codon 301 of the CD2AP protein (p.Lys301Met). This variant is present in population databases (rs141778404, gnomAD 0.2%). This missense change has been observed in individual(s) with chronic kidney disease and/or focal segmental glomerulosclerosis (PMID: 19131354, 26346198, 36134775). ClinVar contains an entry for this variant (Variation ID: 402519). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects CD2AP function (PMID: 19131354). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Breakthrough Genomics, Breakthrough Genomics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

not specified

Uncertain:1

Mar 29, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: AD condition. Extract From Al-Hamed 2013: In addition, the CD2AP variant K301M was found as a heterozygous allele in three of our patients; one was associated with homozygous Q1020X mutation in PLCE1 gene (F5), other two (S14 and S16) were detected alone (Table 5). Although K301M has been reported by Gigante et al.54 previously as a pathogenic mutation, we also found this variant in 2.79% of our normal controls suggesting that this variant is a polymorphism. The previously reported CD2AP variant p.K301M was found a 23-year-old Italian female presenting with SRNS and FSGS.54 The same mutation was found in her 6-year-old child who was reported as phenotypically normal. Functional studies showed that at K301M variant had a defective CD2Ã»CD2AP interaction.54 The high frequency of the K301M variant in the Saudi population would certainly point away from this heterozygous variant alone being disease causing. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.55

BayesDel_addAF

Uncertain

0.14

BayesDel_noAF

Pathogenic

0.24

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.41

Eigen

Pathogenic

0.87

Eigen_PC

Pathogenic

0.82

FATHMM_MKL

Pathogenic

1.0

LIST_S2

Uncertain

0.87

M_CAP

Uncertain

0.13

MetaRNN

Uncertain

0.72

MetaSVM

Uncertain

-0.18

MutationAssessor

Uncertain

2.4

PhyloP100

7.1

PrimateAI

Uncertain

0.62

PROVEAN

Pathogenic

-5.5

REVEL

Pathogenic

0.80

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0010

Polyphen

1.0

Vest4

0.93

MVP

0.90

MPC

0.48

ClinPred

0.63

GERP RS

5.6

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

2.8

Varity_R

0.78

gMVP

0.71

Mutation Taster

=30/70

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

0.99

dbscSNV1_RF

Benign

0.65

SpliceAI score (max)

0.040

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over