rs76153148

chr6-47576998-C-Achr6-47576998-C-G

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BA1

The NM_012120.3(CD2AP):c.809-11C>A variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0021 in 1,311,452 control chromosomes in the GnomAD database, including 64 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0019 (7 hom., cov: 32)
  • Exomes 𝑓: 0.0021 (57 hom.)
• Consequence: CD2AP NM_012120.3 splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.005442
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.529

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]

ACMG classification

Verdict is Benign. Variant got -18 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.46).
• BP6: Variant 6-47576998-C-A is Benign according to our data. Variant chr6-47576998-C-A is described in ClinVar as [Benign]. Clinvar id is 260193.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-47576998-C-A is described in Lovd as [Likely_benign].
• BA1: GnomAdExome4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0511 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CD2AP	NM_012120.3	c.809-11C>A		splice_polypyrimidine_tract_variant, intron_variant		ENST00000359314.5
CD2AP	XM_005248976.2	c.797-11C>A		splice_polypyrimidine_tract_variant, intron_variant
CD2AP	XM_011514449.3	c.662-11C>A		splice_polypyrimidine_tract_variant, intron_variant
CD2AP	XM_017010641.2	c.809-11C>A		splice_polypyrimidine_tract_variant, intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CD2AP	ENST00000359314.5	c.809-11C>A		splice_polypyrimidine_tract_variant, intron_variant		1	NM_012120.3	P1
CD2AP	ENST00000463175.1	n.91-11C>A		splice_polypyrimidine_tract_variant, intron_variant, non_coding_transcript_variant		2

Frequencies

GnomAD3 genomes AF: 0.00190 AC: 289 AN: 152054 Hom.: 7 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0385

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00652

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000191

Gnomad OTH AF: 0.00144

GnomAD3 exomes AF: 0.00352 AC: 882 AN: 250852 Hom.: 18 AF XY: 0.00331 AC XY: 449 AN XY: 135650

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0412

Gnomad SAS exome AF: 0.000164

Gnomad FIN exome AF: 0.00370

Gnomad NFE exome AF: 0.000265

Gnomad OTH exome AF: 0.00147

GnomAD4 exome AF: 0.00212 AC: 2463 AN: 1159280 Hom.: 57 Cov.: 17 AF XY: 0.00203 AC XY: 1200 AN XY: 592302

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000451

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0530

Gnomad4 SAS exome AF: 0.000175

Gnomad4 FIN exome AF: 0.00370

Gnomad4 NFE exome AF: 0.000153

Gnomad4 OTH exome AF: 0.00193

GnomAD4 genome AF: 0.00190 AC: 289 AN: 152172 Hom.: 7 Cov.: 32 AF XY: 0.00229 AC XY: 170 AN XY: 74396

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.0000654

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.0386

Gnomad4 SAS AF: 0.000415

Gnomad4 FIN AF: 0.00652

Gnomad4 NFE AF: 0.000191

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.000426 Hom.: 0

Bravo AF: 0.00152

Asia WGS AF: 0.0140 AC: 50 AN: 3470

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Focal segmental glomerulosclerosis 3, susceptibility to Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

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

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

-

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Aug 30, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.46
Cadd	Benign	9.5
Dann	Benign	0.74

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0054
dbscSNV1_RF	Benign	0.22
SpliceAI score (max)		0.020		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: rs76153148; hg19: chr6-47544734;