6-47595956-C-T

Variant names:

• chr6-47595956-C-T
• rs2039503
• NM_012120.3:c.1204C>T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_012120.3(CD2AP):​c.1204C>T​(p.Leu402Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.997 in 1,612,860 control chromosomes in the GnomAD database, including 801,087 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.98 (73392 hom., cov: 30)
  • Exomes 𝑓: 1.0 (727695 hom.)
• Consequence: CD2AP NM_012120.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -0.222
• Publications: 19 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: Ambry Genetics, Labcorp Genetics (formerly Invitae), ClinGen
• 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=-0.65).
• BP6: Variant 6-47595956-C-T is Benign according to our data. Variant chr6-47595956-C-T is described in ClinVar as Benign. ClinVar VariationId is 260181.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.222 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.994 is higher than 0.05.

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.1204C>T	p.Leu402Leu	synonymous	Exon 12 of 18	NP_036252.1	Q9Y5K6

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CD2AP	ENST00000359314.5	TSL:1 MANE Select	c.1204C>T	p.Leu402Leu	synonymous	Exon 12 of 18	ENSP00000352264.5	Q9Y5K6
	CD2AP	ENST00000865253.1		c.1207C>T	p.Leu403Leu	synonymous	Exon 12 of 18	ENSP00000535312.1
	CD2AP	ENST00000931707.1		c.1195C>T	p.Leu399Leu	synonymous	Exon 12 of 18	ENSP00000601766.1

Frequencies

GnomAD3 genomes AF: 0.982 AC: 149241 AN: 152010 Hom.: 73335 Cov.: 30

Gnomad AFR AF: 0.936

Gnomad AMI AF: 1.00

Gnomad AMR AF: 0.993

Gnomad ASJ AF: 1.00

Gnomad EAS AF: 1.00

Gnomad SAS AF: 1.00

Gnomad FIN AF: 1.00

Gnomad MID AF: 1.00

Gnomad NFE AF: 1.00

Gnomad OTH AF: 0.991

GnomAD2 exomes AF: 0.995 AC: 250173 AN: 251418 AF XY: 0.996

Gnomad AFR exome AF: 0.932

Gnomad AMR exome AF: 0.997

Gnomad ASJ exome AF: 1.00

Gnomad EAS exome AF: 1.00

Gnomad FIN exome AF: 1.00

Gnomad NFE exome AF: 1.00

Gnomad OTH exome AF: 0.999

GnomAD4 exome AF: 0.998 AC: 1457979 AN: 1460732 Hom.: 727695 Cov.: 39 AF XY: 0.998 AC XY: 725563 AN XY: 726760

African (AFR) AF: 0.931 AC: 31127 AN: 33416

American (AMR) AF: 0.997 AC: 44565 AN: 44700

Ashkenazi Jewish (ASJ) AF: 1.00 AC: 26098 AN: 26098

East Asian (EAS) AF: 1.00 AC: 39664 AN: 39664

South Asian (SAS) AF: 1.00 AC: 86203 AN: 86210

European-Finnish (FIN) AF: 1.00 AC: 53414 AN: 53414

Middle Eastern (MID) AF: 0.996 AC: 5740 AN: 5762

European-Non Finnish (NFE) AF: 1.00 AC: 1111049 AN: 1111136

Other (OTH) AF: 0.996 AC: 60119 AN: 60332

GnomAD4 genome AF: 0.982 AC: 149358 AN: 152128 Hom.: 73392 Cov.: 30 AF XY: 0.983 AC XY: 73074 AN XY: 74372

African (AFR) AF: 0.937 AC: 38872 AN: 41502

American (AMR) AF: 0.993 AC: 15161 AN: 15268

Ashkenazi Jewish (ASJ) AF: 1.00 AC: 3468 AN: 3468

East Asian (EAS) AF: 1.00 AC: 5150 AN: 5150

South Asian (SAS) AF: 1.00 AC: 4804 AN: 4806

European-Finnish (FIN) AF: 1.00 AC: 10614 AN: 10614

Middle Eastern (MID) AF: 1.00 AC: 294 AN: 294

European-Non Finnish (NFE) AF: 1.00 AC: 67992 AN: 68004

Other (OTH) AF: 0.991 AC: 2091 AN: 2110

Alfa AF: 0.992 Hom.: 53739

Bravo AF: 0.979

Asia WGS AF: 0.997 AC: 3465 AN: 3476

EpiCase AF: 1.00

EpiControl AF: 1.00

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	Focal segmental glomerulosclerosis 3, susceptibility to (3)
-	-	3	not specified (3)
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.65
CADD	Benign	3.0
DANN	Benign	0.64
PhyloP100		-0.22
Mutation Taster		=100/0	polymorphism (auto)

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: rs2039503; hg19: chr6-47563692; COSMIC: COSV108180985;