rs7749045

Variant names:

• chr6-47533655-A-G
• rs7749045
• NM_012120.3:c.219A>G

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_012120.3(CD2AP):​c.219A>G​(p.Glu73Glu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00146 in 1,614,094 control chromosomes in the GnomAD database, including 28 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0079 (13 hom., cov: 33)
  • Exomes 𝑓: 0.00079 (15 hom.)
• Consequence: CD2AP NM_012120.3 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.926
• 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: AR, AD Classification: DEFINITIVE, STRONG, LIMITED Submitted by: ClinGen, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• inherited focal segmental glomerulosclerosis

  Inheritance: AD Classification: MODERATE Submitted by: ClinGen
• familial idiopathic steroid-resistant nephrotic syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.61).
• BP6: Variant 6-47533655-A-G is Benign according to our data. Variant chr6-47533655-A-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 260189.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.926 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00787 (1199/152330) while in subpopulation AFR AF = 0.0269 (1119/41580). AF 95% confidence interval is 0.0256. There are 13 homozygotes in GnomAd4. There are 578 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 13 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CD2AP	NM_012120.3	MANE Select	c.219A>G	p.Glu73Glu	synonymous	Exon 3 of 18	NP_036252.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CD2AP	ENST00000359314.5	TSL:1 MANE Select	c.219A>G	p.Glu73Glu	synonymous	Exon 3 of 18	ENSP00000352264.5
	CD2AP	ENST00000865253.1		c.219A>G	p.Glu73Glu	synonymous	Exon 3 of 18	ENSP00000535312.1
	CD2AP	ENST00000931707.1		c.219A>G	p.Glu73Glu	synonymous	Exon 3 of 18	ENSP00000601766.1

Frequencies

GnomAD3 genomes AF: 0.00784 AC: 1193 AN: 152212 Hom.: 13 Cov.: 33

Gnomad AFR AF: 0.0268

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00393

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00814

GnomAD2 exomes AF: 0.00213 AC: 536 AN: 251296 AF XY: 0.00145

Gnomad AFR exome AF: 0.0292

Gnomad AMR exome AF: 0.00150

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000264

Gnomad OTH exome AF: 0.000816

GnomAD4 exome AF: 0.000793 AC: 1159 AN: 1461764 Hom.: 15 Cov.: 31 AF XY: 0.000678 AC XY: 493 AN XY: 727182

African (AFR) AF: 0.0301 AC: 1007 AN: 33474

American (AMR) AF: 0.00143 AC: 64 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26130

East Asian (EAS) AF: 0.00 AC: 0 AN: 39678

South Asian (SAS) AF: 0.0000580 AC: 5 AN: 86248

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53394

Middle Eastern (MID) AF: 0.000694 AC: 4 AN: 5766

European-Non Finnish (NFE) AF: 0.00000450 AC: 5 AN: 1111960

Other (OTH) AF: 0.00123 AC: 74 AN: 60390

GnomAD4 genome AF: 0.00787 AC: 1199 AN: 152330 Hom.: 13 Cov.: 33 AF XY: 0.00776 AC XY: 578 AN XY: 74488

African (AFR) AF: 0.0269 AC: 1119 AN: 41580

American (AMR) AF: 0.00392 AC: 60 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000441 AC: 3 AN: 68028

Other (OTH) AF: 0.00806 AC: 17 AN: 2110

Alfa AF: 0.00308 Hom.: 5

Bravo AF: 0.00901

Asia WGS AF: 0.000866 AC: 3 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 (1)
-	-	1	Focal segmental glomerulosclerosis 3, susceptibility to (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.61
CADD	Benign	8.5
DANN	Benign	0.62
PhyloP100		0.93
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=100/0	polymorphism

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

Other links and lift over

dbSNP: rs7749045; hg19: chr6-47501391;