12-100283145-C-G

Variant names:

• chr12-100283145-C-G
• NM_017988.6:c.175C>G

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_017988.6(SCYL2):​c.175C>G​(p.Gln59Glu) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Q59R) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: SCYL2 NM_017988.6 missense, splice_region
• Scores: Splicing: ADA: 0.8773
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.62
• 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: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

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.175C>G	p.Gln59Glu	missense splice_region	Exon 2 of 18	NP_060458.3
	SCYL2	NM_001330253.2		c.175C>G	p.Gln59Glu	missense splice_region	Exon 2 of 19	NP_001317182.1	A0A0U1RQQ9
	SCYL2	NM_001330254.2		c.175C>G	p.Gln59Glu	missense 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.175C>G	p.Gln59Glu	missense splice_region	Exon 2 of 18	ENSP00000354061.2	Q6P3W7
	SCYL2	ENST00000930683.1		c.175C>G	p.Gln59Glu	missense splice_region	Exon 2 of 19	ENSP00000600742.1
	SCYL2	ENST00000635101.1	TSL:5	c.175C>G	p.Gln59Glu	missense 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: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.40
BayesDel_addAF	Pathogenic	0.17	D
BayesDel_noAF	Uncertain	0.010
CADD	Uncertain	25
DANN	Uncertain	0.98
DEOGEN2	Benign	0.015	T
Eigen	Benign	0.091
Eigen_PC	Uncertain	0.24
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.96	D
M_CAP	Benign	0.040	D
MetaRNN	Uncertain	0.50	T
MetaSVM	Benign	-0.45	T
MutationAssessor	Benign	0.95	L
PhyloP100		7.6
PrimateAI	Uncertain	0.79	T
PROVEAN	Benign	-1.7	N
REVEL	Uncertain	0.53
Sift	Benign	0.060	T
Sift4G	Benign	0.10	T
Polyphen		0.37	B
Vest4		0.58
MutPred		0.48		Gain of ubiquitination at K55 (P = 0.0442)
MVP		0.86
MPC		0.24
ClinPred		0.89	D
GERP RS		5.0
Varity_R		0.31
gMVP		0.71
Mutation Taster		=53/47	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.88
dbscSNV1_RF	Benign	0.54
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

hg19: chr12-100676923;