rs77917916

Variant names:

• chr6-47608036-G-T
• rs77917916
• NM_012120.3:c.1632+8G>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_012120.3(CD2AP):​c.1632+8G>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00763 in 1,586,924 control chromosomes in the GnomAD database, including 114 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.014 (36 hom., cov: 32)
  • Exomes 𝑓: 0.0069 (78 hom.)
• Consequence: CD2AP NM_012120.3 splice_region, intron
• Scores: Splicing: ADA: 0.0001126
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -0.140
• Publications: 2 publications found

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 Gene-Disease associations (from GenCC):

• focal segmental glomerulosclerosis 3, susceptibility to

  Inheritance: AD, AR Classification: STRONG, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics
• familial idiopathic steroid-resistant nephrotic syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 6-47608036-G-T is Benign according to our data. Variant chr6-47608036-G-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 260186.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0141 (2148/152162) while in subpopulation AFR AF = 0.0339 (1407/41530). AF 95% confidence interval is 0.0324. There are 36 homozygotes in GnomAd4. There are 1033 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 36 AD,AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_012120.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CD2AP	NM_012120.3	MANE Select	c.1632+8G>T		splice_region intron	N/A	NP_036252.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CD2AP	ENST00000359314.5	TSL:1 MANE Select	c.1632+8G>T		splice_region intron	N/A	ENSP00000352264.5
	CD2AP	ENST00000865253.1		c.1635+8G>T		splice_region intron	N/A	ENSP00000535312.1
	CD2AP	ENST00000931707.1		c.1623+8G>T		splice_region intron	N/A	ENSP00000601766.1

Frequencies

GnomAD3 genomes AF: 0.0141 AC: 2145 AN: 152044 Hom.: 36 Cov.: 32

Gnomad AFR AF: 0.0339

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00603

Gnomad ASJ AF: 0.0141

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0235

Gnomad FIN AF: 0.00207

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00627

Gnomad OTH AF: 0.0182

GnomAD2 exomes AF: 0.00908 AC: 2274 AN: 250394 AF XY: 0.00922

Gnomad AFR exome AF: 0.0352

Gnomad AMR exome AF: 0.00603

Gnomad ASJ exome AF: 0.0162

Gnomad EAS exome AF: 0.000109

Gnomad FIN exome AF: 0.000886

Gnomad NFE exome AF: 0.00522

Gnomad OTH exome AF: 0.00836

GnomAD4 exome AF: 0.00694 AC: 9954 AN: 1434762 Hom.: 78 Cov.: 25 AF XY: 0.00730 AC XY: 5219 AN XY: 715264

African (AFR) AF: 0.0331 AC: 1088 AN: 32886

American (AMR) AF: 0.00600 AC: 268 AN: 44642

Ashkenazi Jewish (ASJ) AF: 0.0154 AC: 399 AN: 25928

East Asian (EAS) AF: 0.0000760 AC: 3 AN: 39466

South Asian (SAS) AF: 0.0212 AC: 1821 AN: 85726

European-Finnish (FIN) AF: 0.00122 AC: 65 AN: 53194

Middle Eastern (MID) AF: 0.0137 AC: 78 AN: 5710

European-Non Finnish (NFE) AF: 0.00523 AC: 5684 AN: 1087718

Other (OTH) AF: 0.00921 AC: 548 AN: 59492

GnomAD4 genome AF: 0.0141 AC: 2148 AN: 152162 Hom.: 36 Cov.: 32 AF XY: 0.0139 AC XY: 1033 AN XY: 74398

African (AFR) AF: 0.0339 AC: 1407 AN: 41530

American (AMR) AF: 0.00602 AC: 92 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.0141 AC: 49 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.0235 AC: 113 AN: 4814

European-Finnish (FIN) AF: 0.00207 AC: 22 AN: 10612

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.00627 AC: 426 AN: 67960

Other (OTH) AF: 0.0180 AC: 38 AN: 2112

Alfa AF: 0.00868 Hom.: 4

Bravo AF: 0.0146

Asia WGS AF: 0.0140 AC: 48 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	1	Focal segmental glomerulosclerosis 3, susceptibility to (1)
-	-	1	Kidney disorder (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	3.5
DANN	Benign	0.58
PhyloP100		-0.14
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00011
dbscSNV1_RF	Benign	0.0
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

Other links and lift over

dbSNP: rs77917916; hg19: chr6-47575772; COSMIC: COSV107459859;