6-47478053-A-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_012120.3(CD2AP):c.-192A>C variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.59 in 701,490 control chromosomes in the GnomAD database, including 123,905 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.58 (25882 hom., cov: 31)
  • Exomes 𝑓: 0.59 (98023 hom.)
• Consequence: CD2AP NM_012120.3 5_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.928

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-DT (HGNC:55263): (CD2AP divergent transcript)

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.96).
• BP6: Variant 6-47478053-A-C is Benign according to our data. Variant chr6-47478053-A-C is described in ClinVar as [Benign]. Clinvar id is 357157.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-47478053-A-C is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.796 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CD2AP	NM_012120.3	c.-192A>C		5_prime_UTR_variant	1/18	ENST00000359314.5
CD2AP	XM_005248976.2	c.-192A>C		5_prime_UTR_variant	1/18
CD2AP	XM_017010641.2	c.-192A>C		5_prime_UTR_variant	1/14

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CD2AP	ENST00000359314.5	c.-192A>C		5_prime_UTR_variant	1/18	1	NM_012120.3	P1
CD2AP-DT	ENST00000604014.2	n.108T>G		non_coding_transcript_exon_variant	1/1

Frequencies

GnomAD3 genomes AF: 0.580 AC: 87936 AN: 151648 Hom.: 25842 Cov.: 31

Gnomad AFR AF: 0.516

Gnomad AMI AF: 0.612

Gnomad AMR AF: 0.675

Gnomad ASJ AF: 0.505

Gnomad EAS AF: 0.817

Gnomad SAS AF: 0.548

Gnomad FIN AF: 0.606

Gnomad MID AF: 0.446

Gnomad NFE AF: 0.582

Gnomad OTH AF: 0.556

GnomAD4 exome AF: 0.592 AC: 325568 AN: 549722 Hom.: 98023 Cov.: 7 AF XY: 0.587 AC XY: 168891 AN XY: 287626

Gnomad4 AFR exome AF: 0.513

Gnomad4 AMR exome AF: 0.722

Gnomad4 ASJ exome AF: 0.494

Gnomad4 EAS exome AF: 0.812

Gnomad4 SAS exome AF: 0.528

Gnomad4 FIN exome AF: 0.593

Gnomad4 NFE exome AF: 0.583

Gnomad4 OTH exome AF: 0.582

GnomAD4 genome AF: 0.580 AC: 88027 AN: 151768 Hom.: 25882 Cov.: 31 AF XY: 0.586 AC XY: 43448 AN XY: 74150

Gnomad4 AFR AF: 0.517

Gnomad4 AMR AF: 0.676

Gnomad4 ASJ AF: 0.505

Gnomad4 EAS AF: 0.817

Gnomad4 SAS AF: 0.548

Gnomad4 FIN AF: 0.606

Gnomad4 NFE AF: 0.582

Gnomad4 OTH AF: 0.560

Alfa AF: 0.537 Hom.: 4852

Bravo AF: 0.583

Asia WGS AF: 0.686 AC: 2385 AN: 3476

ClinVar

Significance: Benign

Submissions summary: Benign:2

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 13, 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 provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Nov 10, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.96
Cadd	Benign	4.0
Dann	Benign	0.38
RBP_binding_hub_radar		0.92
RBP_regulation_power_radar		2.0

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

LitVar

Other links and lift over

dbSNP: rs1056434; hg19: chr6-47445789;