chr6-47577102-A-T

Position:

• chr6-47577102-A-T

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BS1_Supporting BS2

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

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 (HGNC:):

ACMG classification

Verdict is Likely_benign. Variant got -5 ACMG points.

• BS1: Variant frequency is greater than expected in population mid. gnomad4_exome 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 gnomad4_exome. There are 139 alleles in male gnomad4_exome subpopulation. Median coverage is 21. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High Homozygotes in GnomAdExome4 at 5 AR gene

Transcripts

RefSeq

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

Ensembl

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

Frequencies

GnomAD3 genomes AF: 0.000151 AC: 23 AN: 152144 Hom.: 0 Cov.: 32

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

GnomAD3 exomes AF: 0.000191 AC: 48 AN: 250902 Hom.: 0 AF XY: 0.000258 AC XY: 35 AN XY: 135644

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 SAS exome AF: 0.0000984

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.: 5 Cov.: 21 AF XY: 0.000210 AC XY: 139 AN XY: 661250

Gnomad4 AFR exome AF: 0.000458

Gnomad4 AMR exome AF: 0.0000674

Gnomad4 ASJ exome AF: 0.00131

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000846

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000870

Gnomad4 OTH exome AF: 0.000379

GnomAD4 genome AF: 0.000144 AC: 22 AN: 152262 Hom.: 0 Cov.: 32 AF XY: 0.000175 AC XY: 13 AN XY: 74444

Gnomad4 AFR AF: 0.0000722

Gnomad4 AMR AF: 0.0000654

Gnomad4 ASJ AF: 0.000576

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000588

Gnomad4 OTH AF: 0.00189

Alfa AF: 0.000268 Hom.: 0

Bravo AF: 0.0000907

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000349 AC: 3

ExAC AF: 0.000214 AC: 26

Asia WGS AF: 0.000578 AC: 2 AN: 3474

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Focal segmental glomerulosclerosis 3, susceptibility to Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Baylor Genetics	Dec 24, 2019	This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. -
Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Mar 23, 2020	- -

not provided Uncertain:2

Uncertain significance, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Nov 15, 2023	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. -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Mar 29, 2016

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 CD2ûCD2AP 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	D
BayesDel_noAF	Pathogenic	0.24
CADD	Pathogenic	33
DANN	Uncertain	1.0
DEOGEN2	Benign	0.41	T
Eigen	Pathogenic	0.87
Eigen_PC	Pathogenic	0.82
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.87	D
M_CAP	Uncertain	0.13	D
MetaRNN	Uncertain	0.72	D
MetaSVM	Uncertain	-0.18	T
MutationAssessor	Uncertain	2.4	M
PrimateAI	Uncertain	0.62	T
PROVEAN	Pathogenic	-5.5	D
REVEL	Pathogenic	0.80
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0010	D
Polyphen		1.0	D
Vest4		0.93
MVP		0.90
MPC		0.48
ClinPred		0.63	D
GERP RS		5.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.8
Varity_R		0.78
gMVP		0.71

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

LitVar

Other links and lift over

dbSNP: rs141778404; hg19: chr6-47544838;