chr6-47595956-C-G

Variant names:

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

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_012120.3(CD2AP):​c.1204C>G​(p.Leu402Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as (no stars). Synonymous variant affecting the same amino acid position (i.e. L402L) has been classified as Benign.

• Frequency:
  • Genomes: not found (cov: 30)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: CD2AP NM_012120.3 missense
• Clinical Significance: Not reported in ClinVar
• 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: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.36129725).

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>G	p.Leu402Val	missense	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>G	p.Leu402Val	missense	Exon 12 of 18	ENSP00000352264.5	Q9Y5K6
	CD2AP	ENST00000865253.1		c.1207C>G	p.Leu403Val	missense	Exon 12 of 18	ENSP00000535312.1
	CD2AP	ENST00000931707.1		c.1195C>G	p.Leu399Val	missense	Exon 12 of 18	ENSP00000601766.1

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1460738 Hom.: 0 Cov.: 39 AF XY: 0.00 AC XY: 0 AN XY: 726758

African (AFR) AF: 0.00 AC: 0 AN: 33426

American (AMR) AF: 0.00 AC: 0 AN: 44700

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26098

East Asian (EAS) AF: 0.00 AC: 0 AN: 39664

South Asian (SAS) AF: 0.00 AC: 0 AN: 86210

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53414

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5762

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111132

Other (OTH) AF: 0.00 AC: 0 AN: 60332

GnomAD4 genome Cov.: 30

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.081
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Benign	-0.53
CADD	Benign	16
DANN	Uncertain	1.0
DEOGEN2	Benign	0.31	T
Eigen	Benign	-0.27
Eigen_PC	Benign	-0.43
FATHMM_MKL	Benign	0.35	N
LIST_S2	Benign	0.78	T
M_CAP	Benign	0.010	T
MetaRNN	Benign	0.36	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.8	M
PhyloP100		-0.22
PrimateAI	Uncertain	0.49	T
PROVEAN	Benign	-1.2	N
REVEL	Benign	0.11
Sift	Benign	0.042	D
Sift4G	Benign	0.078	T
Polyphen		1.0	D
Vest4		0.16
MutPred		0.27		Gain of sheet (P = 0.0266)
MVP		0.68
MPC		0.076
ClinPred		0.29	T
GERP RS		-1.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.036
gMVP		0.15
Mutation Taster		=95/5	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: rs2039503; hg19: chr6-47563692;