rs116754410

Variant names:

• chr6-47624205-A-G
• rs116754410
• NM_012120.3:c.1898A>G

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.1898A>G​(p.Lys633Arg) variant causes a missense change. The variant allele was found at a frequency of 0.00145 in 1,612,410 control chromosomes in the GnomAD database, including 29 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. K633I) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0079 (14 hom., cov: 32)
  • Exomes 𝑓: 0.00078 (15 hom.)
• Consequence: CD2AP NM_012120.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 4.56
• Publications: 9 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.008623064).
• BP6: Variant 6-47624205-A-G is Benign according to our data. Variant chr6-47624205-A-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 260188.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 = 0.00787 (1198/152232) while in subpopulation AFR AF = 0.0269 (1118/41560). AF 95% confidence interval is 0.0256. There are 14 homozygotes in GnomAd4. There are 577 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 14 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.1898A>G	p.Lys633Arg	missense	Exon 18 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.1898A>G	p.Lys633Arg	missense	Exon 18 of 18	ENSP00000352264.5	Q9Y5K6
	CD2AP	ENST00000865253.1		c.1901A>G	p.Lys634Arg	missense	Exon 18 of 18	ENSP00000535312.1
	CD2AP	ENST00000931707.1		c.1889A>G	p.Lys630Arg	missense	Exon 18 of 18	ENSP00000601766.1

Frequencies

GnomAD3 genomes AF: 0.00784 AC: 1192 AN: 152114 Hom.: 14 Cov.: 32

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: 534 AN: 251096 AF XY: 0.00145

Gnomad AFR exome AF: 0.0291

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: 0.000817

GnomAD4 exome AF: 0.000778 AC: 1136 AN: 1460178 Hom.: 15 Cov.: 29 AF XY: 0.000658 AC XY: 478 AN XY: 726470

African (AFR) AF: 0.0295 AC: 985 AN: 33396

American (AMR) AF: 0.00143 AC: 64 AN: 44712

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26112

East Asian (EAS) AF: 0.00 AC: 0 AN: 39568

South Asian (SAS) AF: 0.0000580 AC: 5 AN: 86206

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53398

Middle Eastern (MID) AF: 0.000694 AC: 4 AN: 5764

European-Non Finnish (NFE) AF: 0.00000450 AC: 5 AN: 1110696

Other (OTH) AF: 0.00121 AC: 73 AN: 60326

GnomAD4 genome AF: 0.00787 AC: 1198 AN: 152232 Hom.: 14 Cov.: 32 AF XY: 0.00775 AC XY: 577 AN XY: 74434

African (AFR) AF: 0.0269 AC: 1118 AN: 41560

American (AMR) AF: 0.00392 AC: 60 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10610

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

European-Non Finnish (NFE) AF: 0.0000441 AC: 3 AN: 67968

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

Alfa AF: 0.00300 Hom.: 14

Bravo AF: 0.00901

ESP6500AA AF: 0.0259 AC: 114

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00268 AC: 326

Asia WGS AF: 0.000866 AC: 3 AN: 3478

ClinVar

ClinVar submissions

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
AlphaMissense	Benign	0.087
BayesDel_addAF	Benign	-0.49	T
BayesDel_noAF	Benign	-0.45
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.37	T
Eigen	Uncertain	0.57
Eigen_PC	Uncertain	0.53
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.84	T
MetaRNN	Benign	0.0086	T
MetaSVM	Benign	-0.77	T
MutationAssessor	Uncertain	2.6	M
PhyloP100		4.6
PrimateAI	Benign	0.45	T
PROVEAN	Benign	-1.8	N
REVEL	Benign	0.21
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.27
MVP		0.80
MPC		0.32
ClinPred		0.045	T
GERP RS		4.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.25
gMVP		0.10
Mutation Taster		=98/2	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: rs116754410; hg19: chr6-47591941;