12-100311187-A-T

Variant names:

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_017988.6(SCYL2):c.624A>T(p.Glu208Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000296 in 1,586,578 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000032 ( 0 hom. )

Consequence

SCYL2
NM_017988.6 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.374

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.066063315).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SCYL2	NM_017988.6 link	c.624A>T	p.Glu208Asp	missense_variant	Exon 5 of 18	ENST00000360820.7	NP_060458.3	Q6P3W7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
SCYL2	ENST00000360820.7 link	c.624A>T	p.Glu208Asp	missense_variant	Exon 5 of 18	1	NM_017988.6	ENSP00000354061.2	Q6P3W7
SCYL2	ENST00000635101.1 link	c.624A>T	p.Glu208Asp	missense_variant	Exon 5 of 19	5		ENSP00000489123.1	A0A0U1RQQ9
SCYL2	ENST00000549687.5 link	c.624A>T	p.Glu208Asp	missense_variant	Exon 5 of 17	2		ENSP00000448366.1	F8VSC5
SCYL2	ENST00000548392.5 link	c.105A>T	p.Glu35Asp	missense_variant	Exon 4 of 5	4		ENSP00000450294.1	F8VPW3

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152190

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000133

AC:

AN:

224876

Hom.:

AF XY:

0.00000820

AC XY:

AN XY:

121960

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000282

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000321

AC:

AN:

1434388

Hom.:

Cov.:

AF XY:

0.0000280

AC XY:

AN XY:

713188

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000417

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152190

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74342

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.0000654

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000712

Hom.:

Bravo

AF:

0.0000151

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Inborn genetic diseases

Uncertain:1

Mar 18, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.624A>T (p.E208D) alteration is located in exon 5 (coding exon 4) of the SCYL2 gene. This alteration results from a A to T substitution at nucleotide position 624, causing the glutamic acid (E) at amino acid position 208 to be replaced by an aspartic acid (D). 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

Benign

0.085

BayesDel_addAF

Benign

-0.37

BayesDel_noAF

Benign

-0.69

CADD

Benign

DANN

Benign

0.25

DEOGEN2

Benign

0.0021

T;T;T;T

Eigen

Benign

-0.54

Eigen_PC

Benign

-0.32

FATHMM_MKL

Benign

0.58

LIST_S2

Uncertain

0.87

D;D;D;D

M_CAP

Benign

0.0038

MetaRNN

Benign

0.066

T;T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

-0.24

.;.;.;N

PrimateAI

Uncertain

0.71

PROVEAN

Benign

0.55

N;N;.;N

REVEL

Benign

0.088

Sift

Benign

1.0

T;T;.;T

Sift4G

Benign

0.90

T;T;T;T

Polyphen

0.0

.;.;.;B

Vest4

0.12, 0.12

MutPred

0.33

Gain of catalytic residue at T204 (P = 0.0191);.;Gain of catalytic residue at T204 (P = 0.0191);Gain of catalytic residue at T204 (P = 0.0191);

MVP

0.26

MPC

0.18

ClinPred

0.029

GERP RS

4.0

Varity_R

0.10

gMVP

0.24

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over