6-47477978-G-A

Variant names:

• chr6-47477978-G-A
• rs532229799
• NM_012120.3:c.-267G>A

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_012120.3(CD2AP):​c.-267G>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 0.00146 in 561,740 control chromosomes in the GnomAD database, including 10 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.00082 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0017 (10 hom.)
• Consequence: CD2AP NM_012120.3 5_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.471

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP6: Variant 6-47477978-G-A is Benign according to our data. Variant chr6-47477978-G-A is described in ClinVar as [Benign]. Clinvar id is 357155.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.000815 (124/152074) while in subpopulation SAS AF= 0.00974 (47/4824). AF 95% confidence interval is 0.00753. There are 0 homozygotes in gnomad4. There are 68 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome4 at 10 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CD2AP	NM_012120.3	c.-267G>A		5_prime_UTR_variant	Exon 1 of 18	ENST00000359314.5	NP_036252.1
CD2AP	XM_005248976.2	c.-267G>A		5_prime_UTR_variant	Exon 1 of 18		XP_005249033.1
CD2AP	XM_017010641.2	c.-267G>A		5_prime_UTR_variant	Exon 1 of 14		XP_016866130.1
CD2AP-DT	NR_187257.1	n.95C>T		non_coding_transcript_exon_variant	Exon 1 of 1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CD2AP	ENST00000359314	c.-267G>A		5_prime_UTR_variant	Exon 1 of 18	1	NM_012120.3	ENSP00000352264.5
CD2AP-DT	ENST00000604014.2	n.183C>T		non_coding_transcript_exon_variant	Exon 1 of 1	6

Frequencies

GnomAD3 genomes AF: 0.000823 AC: 125 AN: 151958 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000217

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000851

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000194

Gnomad SAS AF: 0.00994

Gnomad FIN AF: 0.0000948

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000692

Gnomad OTH AF: 0.00240

GnomAD4 exome AF: 0.00170 AC: 698 AN: 409666 Hom.: 10 Cov.: 3 AF XY: 0.00239 AC XY: 517 AN XY: 216032

Gnomad4 AFR exome AF: 0.000219

Gnomad4 AMR exome AF: 0.000488

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000372

Gnomad4 SAS exome AF: 0.0113

Gnomad4 FIN exome AF: 0.000110

Gnomad4 NFE exome AF: 0.000679

Gnomad4 OTH exome AF: 0.000921

GnomAD4 genome AF: 0.000815 AC: 124 AN: 152074 Hom.: 0 Cov.: 32 AF XY: 0.000914 AC XY: 68 AN XY: 74362

Gnomad4 AFR AF: 0.000217

Gnomad4 AMR AF: 0.000850

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000194

Gnomad4 SAS AF: 0.00974

Gnomad4 FIN AF: 0.0000948

Gnomad4 NFE AF: 0.000692

Gnomad4 OTH AF: 0.00237

Alfa AF: 0.000318 Hom.: 0

Bravo AF: 0.000635

Asia WGS AF: 0.00260 AC: 9 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Focal segmental glomerulosclerosis 3, susceptibility to Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	14
DANN	Benign	0.97
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: rs532229799; hg19: chr6-47445714;