12-100312547-T-C

Variant names:

• chr12-100312547-T-C
• NM_017988.6:c.746T>C

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_017988.6(SCYL2):​c.746T>C​(p.Met249Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic 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: 7.82

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 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.832

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SCYL2	NM_017988.6	c.746T>C	p.Met249Thr	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.746T>C	p.Met249Thr	missense_variant	Exon 6 of 18	1	NM_017988.6	ENSP00000354061.2
SCYL2	ENST00000635101.1	c.746T>C	p.Met249Thr	missense_variant	Exon 6 of 19	5		ENSP00000489123.1
SCYL2	ENST00000549687.5	c.746T>C	p.Met249Thr	missense_variant	Exon 6 of 17	2		ENSP00000448366.1
SCYL2	ENST00000548392.5	c.227T>C	p.Met76Thr	missense_variant, splice_region_variant	Exon 5 of 5	4		ENSP00000450294.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

May 03, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.746T>C (p.M249T) alteration is located in exon 6 (coding exon 5) of the SCYL2 gene. This alteration results from a T to C substitution at nucleotide position 746, causing the methionine (M) at amino acid position 249 to be replaced by a threonine (T). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.80
BayesDel_addAF	Pathogenic	0.38	D
BayesDel_noAF	Pathogenic	0.31
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.061	T;T;T;T
Eigen	Uncertain	0.41
Eigen_PC	Uncertain	0.53
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.95	D;T;D;D
M_CAP	Benign	0.047	D
MetaRNN	Pathogenic	0.75	D;D;D;D
MetaSVM	Uncertain	-0.20	T
MutationAssessor	Uncertain	2.7	.;.;.;M
PrimateAI	Pathogenic	0.82	D
PROVEAN	Uncertain	-3.7	D;D;.;D
REVEL	Pathogenic	0.71
Sift	Uncertain	0.0040	D;D;.;D
Sift4G	Uncertain	0.028	D;D;D;D
Polyphen		0.29	.;.;.;B
Vest4		0.91, 0.91
MutPred		0.69		Gain of catalytic residue at S247 (P = 0);.;Gain of catalytic residue at S247 (P = 0);Gain of catalytic residue at S247 (P = 0);
MVP		0.84
MPC		0.75
ClinPred		0.99	D
GERP RS		6.0
Varity_R		0.63
gMVP		0.82

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr12-100706325;