6-47477804-C-G

Position:

• chr6-47477804-C-G

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.-441C>G variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.074 in 201,940 control chromosomes in the GnomAD database, including 636 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.074 (437 hom., cov: 32)
  • Exomes 𝑓: 0.074 (199 hom.)
• Consequence: CD2AP NM_012120.3 5_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.261

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=-0.86).
• BP6: Variant 6-47477804-C-G is Benign according to our data. Variant chr6-47477804-C-G is described in ClinVar as [Benign]. Clinvar id is 357150.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.125 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CD2AP	NM_012120.3	c.-441C>G		5_prime_UTR_variant	1/18	ENST00000359314.5
CD2AP	XM_005248976.2	c.-441C>G		5_prime_UTR_variant	1/18
CD2AP	XM_017010641.2	c.-441C>G		5_prime_UTR_variant	1/14

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CD2AP	ENST00000359314.5	c.-441C>G		5_prime_UTR_variant	1/18	1	NM_012120.3	P1
CD2AP-DT	ENST00000604014.2	n.357G>C		non_coding_transcript_exon_variant	1/1

Frequencies

GnomAD3 genomes AF: 0.0740 AC: 11251 AN: 152038 Hom.: 436 Cov.: 32

Gnomad AFR AF: 0.0629

Gnomad AMI AF: 0.0769

Gnomad AMR AF: 0.0756

Gnomad ASJ AF: 0.118

Gnomad EAS AF: 0.0774

Gnomad SAS AF: 0.134

Gnomad FIN AF: 0.0546

Gnomad MID AF: 0.0633

Gnomad NFE AF: 0.0765

Gnomad OTH AF: 0.0789

GnomAD4 exome AF: 0.0739 AC: 3681 AN: 49784 Hom.: 199 Cov.: 0 AF XY: 0.0790 AC XY: 2055 AN XY: 26022

Gnomad4 AFR exome AF: 0.0541

Gnomad4 AMR exome AF: 0.0653

Gnomad4 ASJ exome AF: 0.0918

Gnomad4 EAS exome AF: 0.0703

Gnomad4 SAS exome AF: 0.112

Gnomad4 FIN exome AF: 0.0621

Gnomad4 NFE exome AF: 0.0665

Gnomad4 OTH exome AF: 0.0712

GnomAD4 genome AF: 0.0740 AC: 11266 AN: 152156 Hom.: 437 Cov.: 32 AF XY: 0.0748 AC XY: 5564 AN XY: 74388

Gnomad4 AFR AF: 0.0631

Gnomad4 AMR AF: 0.0756

Gnomad4 ASJ AF: 0.118

Gnomad4 EAS AF: 0.0774

Gnomad4 SAS AF: 0.133

Gnomad4 FIN AF: 0.0546

Gnomad4 NFE AF: 0.0765

Gnomad4 OTH AF: 0.0805

Alfa AF: 0.0325 Hom.: 21

Bravo AF: 0.0729

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 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 provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Nov 11, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	6.7
DANN	Benign	0.71
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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: rs111766401; hg19: chr6-47445540;