6-47478191-T-A

Position:

• chr6-47478191-T-A

Variant summary

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

The ENST00000359314.5(CD2AP):​c.-54T>A variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.953 in 1,506,244 control chromosomes in the GnomAD database, including 683,268 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.96 (70406 hom., cov: 33)
  • Exomes 𝑓: 0.95 (612862 hom.)
• Consequence: CD2AP ENST00000359314.5 5_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.760

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=-0.85).
• BP6: Variant 6-47478191-T-A is Benign according to our data. Variant chr6-47478191-T-A is described in ClinVar as [Benign]. Clinvar id is 357162.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-47478191-T-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.991 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CD2AP	NM_012120.3	c.-54T>A		5_prime_UTR_variant	1/18	ENST00000359314.5	NP_036252.1
CD2AP	XM_005248976.2	c.-54T>A		5_prime_UTR_variant	1/18		XP_005249033.1
CD2AP	XM_017010641.2	c.-54T>A		5_prime_UTR_variant	1/14		XP_016866130.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CD2AP	ENST00000359314.5	c.-54T>A		5_prime_UTR_variant	1/18	1	NM_012120.3	ENSP00000352264	P1
CD2AP-DT	ENST00000604014.2			upstream_gene_variant

Frequencies

GnomAD3 genomes AF: 0.961 AC: 145951 AN: 151922 Hom.: 70352 Cov.: 33

Gnomad AFR AF: 0.872

Gnomad AMI AF: 1.00

Gnomad AMR AF: 0.978

Gnomad ASJ AF: 0.971

Gnomad EAS AF: 1.00

Gnomad SAS AF: 0.999

Gnomad FIN AF: 0.999

Gnomad MID AF: 0.978

Gnomad NFE AF: 0.998

Gnomad OTH AF: 0.965

GnomAD4 exome AF: 0.952 AC: 1289640 AN: 1354210 Hom.: 612862 Cov.: 41 AF XY: 0.953 AC XY: 637763 AN XY: 669224

Gnomad4 AFR exome AF: 0.828

Gnomad4 AMR exome AF: 0.941

Gnomad4 ASJ exome AF: 0.929

Gnomad4 EAS exome AF: 0.958

Gnomad4 SAS exome AF: 0.956

Gnomad4 FIN exome AF: 0.964

Gnomad4 NFE exome AF: 0.956

Gnomad4 OTH exome AF: 0.945

GnomAD4 genome AF: 0.961 AC: 146061 AN: 152034 Hom.: 70406 Cov.: 33 AF XY: 0.963 AC XY: 71568 AN XY: 74318

Gnomad4 AFR AF: 0.873

Gnomad4 AMR AF: 0.978

Gnomad4 ASJ AF: 0.971

Gnomad4 EAS AF: 1.00

Gnomad4 SAS AF: 0.999

Gnomad4 FIN AF: 0.999

Gnomad4 NFE AF: 0.998

Gnomad4 OTH AF: 0.965

Alfa AF: 0.976 Hom.: 9013

Bravo AF: 0.955

Asia WGS AF: 0.989 AC: 3438 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, criteria provided, single submitter	clinical testing	Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan	Jul 15, 2024	This variant is classified as Benign based on local population frequency. This variant was detected in 100% of patients studied in a panel designed for Epileptic and Developmental Encephalopathy and Progressive Myoclonus Epilepsy. Number of patients: 93. Only high quality variants are reported. -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

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	-0.85
CADD	Benign	6.3
DANN	Benign	0.65
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.1

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: rs9349406; hg19: chr6-47445927;