rs2135832798

Variant names:

• chr12-100283145-C-CA
• rs2135832798
• NM_017988.6:c.176dupA

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_017988.6(SCYL2):​c.176dupA​(p.Glu60GlyfsTer8) variant causes a frameshift, splice region change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: SCYL2 NM_017988.6 frameshift, splice_region
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 8.98
• Publications: 0 publications found

Genes affected

SCYL2 (HGNC:19286): (SCY1 like pseudokinase 2) The protein encoded by this gene associates with clathrin-coated complexes at the plasma membrane and with endocytic coated vesicles. The encoded protein phosphorylates the beta2 subunit of the plasma membrane adapter complex AP2 and interacts with clathrin, showing involvement in clathrin-dependent pathways between the trans-Golgi network and the endosomal system. In addition, this protein has a role in the Wnt signaling pathway by targeting frizzled 5 (Fzd5) for lysosomal degradation. Two transcript variants encoding the same protein have been found for this gene. [provided by RefSeq, Dec 2015]

SCYL2 Gene-Disease associations (from GenCC):

• arthrogryposis multiplex congenita 4, neurogenic, with agenesis of the corpus callosum

  Inheritance: AR Classification: STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, PanelApp Australia

ACMG classification

Our verdict: Pathogenic. The variant received 12 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 12-100283145-C-CA is Pathogenic according to our data. Variant chr12-100283145-C-CA is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 1308644.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_017988.6. 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
	SCYL2	NM_017988.6	MANE Select	c.176dupA	p.Glu60GlyfsTer8	frameshift splice_region	Exon 2 of 18	NP_060458.3
	SCYL2	NM_001330253.2		c.176dupA	p.Glu60GlyfsTer8	frameshift splice_region	Exon 2 of 19	NP_001317182.1	A0A0U1RQQ9
	SCYL2	NM_001330254.2		c.176dupA	p.Glu60GlyfsTer8	frameshift splice_region	Exon 2 of 19	NP_001317183.1	A0A0U1RQQ9

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SCYL2	ENST00000360820.7	TSL:1 MANE Select	c.176dupA	p.Glu60GlyfsTer8	frameshift splice_region	Exon 2 of 18	ENSP00000354061.2	Q6P3W7
	SCYL2	ENST00000930683.1		c.176dupA	p.Glu60GlyfsTer8	frameshift splice_region	Exon 2 of 19	ENSP00000600742.1
	SCYL2	ENST00000635101.1	TSL:5	c.176dupA	p.Glu60GlyfsTer8	frameshift splice_region	Exon 2 of 19	ENSP00000489123.1	A0A0U1RQQ9

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Likely pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
1	-	-	Arthrogryposis multiplex congenita 4, neurogenic, with agenesis of the corpus callosum (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		9.0

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: rs2135832798; hg19: chr12-100676923;