11-65525587-C-T

Variant summary

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

The NM_020680.4(SCYL1):c.125C>T(p.Pro42Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,460,170 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: SCYL1 NM_020680.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.93

Genes affected

SCYL1 (HGNC:14372): (SCY1 like pseudokinase 1) This gene encodes a transcriptional regulator belonging to the SCY1-like family of kinase-like proteins. The protein has a divergent N-terminal kinase domain that is thought to be catalytically inactive, and can bind specific DNA sequences through its C-terminal domain. It activates transcription of the telomerase reverse transcriptase and DNA polymerase beta genes. The protein has been localized to the nucleus, and also to the cytoplasm and centrosomes during mitosis. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

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=0.21037766).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SCYL1	NM_020680.4	c.125C>T	p.Pro42Leu	missense_variant	2/18	ENST00000270176.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SCYL1	ENST00000270176.10	c.125C>T	p.Pro42Leu	missense_variant	2/18	1	NM_020680.4	P1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1460170 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 726366

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: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 04, 2023

The c.125C>T (p.P42L) alteration is located in exon 2 (coding exon 2) of the SCYL1 gene. This alteration results from a C to T substitution at nucleotide position 125, causing the proline (P) at amino acid position 42 to be replaced by a leucine (L). 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	0.067
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Benign	-0.41
Cadd	Benign	14
Dann	Benign	0.76
DEOGEN2	Benign	0.22	T;T;.;.;T
Eigen	Benign	-0.77
Eigen_PC	Benign	-0.78
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Uncertain	0.90	D;D;D;D;D
M_CAP	Benign	0.064	D
MetaRNN	Benign	0.21	T;T;T;T;T
MetaSVM	Benign	-0.71	T
MutationTaster	Benign	0.99	D;N;N;N;N;N;N;N
PrimateAI	Pathogenic	0.82	D
PROVEAN	Uncertain	-4.1	D;D;D;D;D
REVEL	Benign	0.12
Sift	Benign	0.050	D;T;T;T;T
Sift4G	Uncertain	0.023	D;D;D;D;D
Polyphen		0.0060	B;.;B;B;B
Vest4		0.23
MutPred		0.42		Loss of disorder (P = 0.045);Loss of disorder (P = 0.045);Loss of disorder (P = 0.045);Loss of disorder (P = 0.045);Loss of disorder (P = 0.045);
MVP		0.29
MPC		0.37
ClinPred		0.27	T
GERP RS		1.4
Varity_R		0.16
gMVP		0.38

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: chr11-65293058;