rs1554181304

Variant names:

• chr6-47576523-GC-CT
• rs1554181304
• NM_012120.3:c.730-1_730delGCinsCT

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PVS1_Moderate PM2 PP5_Moderate

The NM_012120.3(CD2AP):​c.730-1_730delGCinsCT​(p.Pro244Ser) variant causes a splice acceptor, missense, splice region, intron change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: CD2AP NM_012120.3 splice_acceptor, missense, splice_region, intron
• Clinical Significance: Pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 4.31

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 Likely_pathogenic. Variant got 6 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.041145835 fraction of the gene. Cryptic splice site detected, with MaxEntScore 6.5, offset of 15, new splice context is: tctactccttaatcctacAGtca. Cryptic site results in inframe change. If cryptic site found is not functional and variant results in exon loss, it results in frameshift change.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 6-47576523-GC-CT is Pathogenic according to our data. Variant chr6-47576523-GC-CT is described in ClinVar as [Pathogenic]. Clinvar id is 5703.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CD2AP	NM_012120.3	c.730-1_730delGCinsCT	p.Pro244Ser	splice_acceptor_variant, missense_variant, splice_region_variant, intron_variant		ENST00000359314.5	NP_036252.1
CD2AP	XM_005248976.2	c.730-1_730delGCinsCT	p.Pro244Ser	splice_acceptor_variant, missense_variant, splice_region_variant, intron_variant			XP_005249033.1
CD2AP	XM_011514449.3	c.583-1_583delGCinsCT	p.Pro195Ser	splice_acceptor_variant, missense_variant, splice_region_variant, intron_variant			XP_011512751.1
CD2AP	XM_017010641.2	c.730-1_730delGCinsCT	p.Pro244Ser	splice_acceptor_variant, missense_variant, splice_region_variant, intron_variant			XP_016866130.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CD2AP	ENST00000359314.5	c.730-1_730delGCinsCT	p.Pro244Ser	splice_acceptor_variant, missense_variant, splice_region_variant, intron_variant		1	NM_012120.3	ENSP00000352264.5
CD2AP	ENST00000463175.1	n.11_12delGCinsCT		non_coding_transcript_exon_variant	Exon 1 of 3	2

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

Focal segmental glomerulosclerosis 3, susceptibility to Pathogenic:1

Mar 26, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Focal segmental glomerulosclerosis 3 Pathogenic:1

May 23, 2003

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1554181304; hg19: chr6-47544259;