rs77917916

Variant names:

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

Variant summary

Our verdict is Benign. Variant got -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

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]

ACMG classification

Verdict is Benign. Variant got -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 [Likely_benign]. Clinvar id is 260186.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-47608036-G-T is described in Lovd as [Benign].
• 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 male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 36 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CD2AP	NM_012120.3	c.1632+8G>T		splice_region_variant, intron_variant	Intron 15 of 17	ENST00000359314.5	NP_036252.1
CD2AP	XM_005248976.2	c.1620+8G>T		splice_region_variant, intron_variant	Intron 15 of 17		XP_005249033.1
CD2AP	XM_011514449.3	c.1485+8G>T		splice_region_variant, intron_variant	Intron 14 of 16		XP_011512751.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CD2AP	ENST00000359314.5	c.1632+8G>T		splice_region_variant, intron_variant	Intron 15 of 17	1	NM_012120.3	ENSP00000352264.5
CD2AP	ENST00000486693.1	n.157+8G>T		splice_region_variant, intron_variant	Intron 1 of 1	4

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

GnomAD3 exomes AF: 0.00908 AC: 2274 AN: 250394 Hom.: 29 AF XY: 0.00922 AC XY: 1248 AN XY: 135310

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 SAS exome AF: 0.0219

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

Gnomad4 AFR exome AF: 0.0331

Gnomad4 AMR exome AF: 0.00600

Gnomad4 ASJ exome AF: 0.0154

Gnomad4 EAS exome AF: 0.0000760

Gnomad4 SAS exome AF: 0.0212

Gnomad4 FIN exome AF: 0.00122

Gnomad4 NFE exome AF: 0.00523

Gnomad4 OTH exome AF: 0.00921

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

Gnomad4 AFR AF: 0.0339

Gnomad4 AMR AF: 0.00602

Gnomad4 ASJ AF: 0.0141

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.0235

Gnomad4 FIN AF: 0.00207

Gnomad4 NFE AF: 0.00627

Gnomad4 OTH AF: 0.0180

Alfa AF: 0.00882 Hom.: 3

Bravo AF: 0.0146

Asia WGS AF: 0.0140 AC: 48 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Apr 20, 2020

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 16, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Benign:1

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Focal segmental glomerulosclerosis 3, susceptibility to Benign:1

Jan 12, 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. -

Kidney disorder Benign:1

Sep 07, 2022

Genome Diagnostics Laboratory, The Hospital for Sick Children

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	3.5
DANN	Benign	0.58
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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

Publications

LitVar

Other links and lift over

dbSNP: rs77917916; hg19: chr6-47575772;