6-47478048-C-T

Position:

• chr6-47478048-C-T

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BS1_Supporting BS2

The NM_012120.3(CD2AP):​c.-197C>T variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000617 in 685,590 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.00038 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00068 (2 hom.)
• Consequence: CD2AP NM_012120.3 5_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 0.883

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 -9 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BS1: Variant frequency is greater than expected in population mid. gnomad4_exome allele frequency = 0.000684 (365/533384) while in subpopulation MID AF= 0.000917 (2/2180). AF 95% confidence interval is 0.000357. There are 2 homozygotes in gnomad4_exome. There are 196 alleles in male gnomad4_exome subpopulation. Median coverage is 7. 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 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CD2AP	NM_012120.3	c.-197C>T		5_prime_UTR_variant	1/18	ENST00000359314.5
CD2AP	XM_005248976.2	c.-197C>T		5_prime_UTR_variant	1/18
CD2AP	XM_017010641.2	c.-197C>T		5_prime_UTR_variant	1/14

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CD2AP	ENST00000359314.5	c.-197C>T		5_prime_UTR_variant	1/18	1	NM_012120.3	P1
CD2AP-DT	ENST00000604014.2	n.113G>A		non_coding_transcript_exon_variant	1/1

Frequencies

GnomAD3 genomes AF: 0.000381 AC: 58 AN: 152088 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.0121

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000162

Gnomad OTH AF: 0.000958

GnomAD4 exome AF: 0.000684 AC: 365 AN: 533384 Hom.: 2 Cov.: 7 AF XY: 0.000701 AC XY: 196 AN XY: 279684

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000479

Gnomad4 ASJ exome AF: 0.0169

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000514

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000179

Gnomad4 OTH exome AF: 0.00101

GnomAD4 genome AF: 0.000381 AC: 58 AN: 152206 Hom.: 0 Cov.: 32 AF XY: 0.000390 AC XY: 29 AN XY: 74400

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.0000653

Gnomad4 ASJ AF: 0.0121

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000208

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000162

Gnomad4 OTH AF: 0.000948

Alfa AF: 0.000555 Hom.: 0

Bravo AF: 0.000495

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Focal segmental glomerulosclerosis 3, susceptibility to Uncertain:1

Uncertain significance, 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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	7.2
DANN	Benign	0.80
RBP_binding_hub_radar		0.97
RBP_regulation_power_radar		2.1

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs886061513; hg19: chr6-47445784;