12-100312519-T-G

Variant names:

• chr12-100312519-T-G
• rs2096343406
• NM_017988.6:c.718T>G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_017988.6(SCYL2):​c.718T>G​(p.Ser240Ala) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: SCYL2 NM_017988.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.03

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.24926919).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SCYL2	NM_017988.6	c.718T>G	p.Ser240Ala	missense_variant	Exon 6 of 18	ENST00000360820.7	NP_060458.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SCYL2	ENST00000360820.7	c.718T>G	p.Ser240Ala	missense_variant	Exon 6 of 18	1	NM_017988.6	ENSP00000354061.2
SCYL2	ENST00000635101.1	c.718T>G	p.Ser240Ala	missense_variant	Exon 6 of 19	5		ENSP00000489123.1
SCYL2	ENST00000549687.5	c.718T>G	p.Ser240Ala	missense_variant	Exon 6 of 17	2		ENSP00000448366.1
SCYL2	ENST00000548392.5	c.199T>G	p.Ser67Ala	missense_variant	Exon 5 of 5	4		ENSP00000450294.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Jan 18, 2024

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.024	T
BayesDel_noAF	Benign	-0.27
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.0099	T;T;T;T
Eigen	Benign	-0.047
Eigen_PC	Benign	0.16
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.71	T;T;T;T
M_CAP	Benign	0.020	T
MetaRNN	Benign	0.25	T;T;T;T
MetaSVM	Benign	-0.75	T
MutationAssessor	Benign	1.5	.;.;.;L
PrimateAI	Pathogenic	0.85	D
PROVEAN	Benign	-0.88	N;N;.;N
REVEL	Benign	0.20
Sift	Benign	0.49	T;T;.;T
Sift4G	Benign	0.75	T;T;T;T
Polyphen		0.0030	.;.;.;B
Vest4		0.39, 0.37
MutPred		0.42		Gain of catalytic residue at T245 (P = 0);.;Gain of catalytic residue at T245 (P = 0);Gain of catalytic residue at T245 (P = 0);
MVP		0.55
MPC		0.16
ClinPred		0.80	D
GERP RS		5.7
Varity_R		0.15
gMVP		0.39

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs2096343406; hg19: chr12-100706297;