rs942522644

Variant names:

• chr11-65525982-C-T
• rs942522644
• NM_020680.4:c.314C>T

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PM2 PP3_Moderate PP5

The NM_020680.4(SCYL1):​c.314C>T​(p.Ala105Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000062 in 1,613,346 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/23 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A105T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 31)
  • Exomes 𝑓: 0.0000062 (0 hom.)
• Consequence: SCYL1 NM_020680.4 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:2
• Conservation: PhyloP100: 0.974
• Publications: 3 publications found

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]

SCYL1 Gene-Disease associations (from GenCC):

• acute infantile liver failure-cerebellar ataxia-peripheral sensory motor neuropathy syndrome

  Inheritance: AR Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics, PanelApp Australia, Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• PP5: Variant 11-65525982-C-T is Pathogenic according to our data. Variant chr11-65525982-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 446294.Status of the report is no_assertion_criteria_provided, 0 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_020680.4. 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
	SCYL1	NM_020680.4	MANE Select	c.314C>T	p.Ala105Val	missense	Exon 3 of 18	NP_065731.3
	SCYL1	NM_001425179.1		c.314C>T	p.Ala105Val	missense	Exon 3 of 18	NP_001412108.1
	SCYL1	NM_001425180.1		c.314C>T	p.Ala105Val	missense	Exon 3 of 18	NP_001412109.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SCYL1	ENST00000270176.10	TSL:1 MANE Select	c.314C>T	p.Ala105Val	missense	Exon 3 of 18	ENSP00000270176.5	Q96KG9-1
	SCYL1	ENST00000420247.6	TSL:1	c.314C>T	p.Ala105Val	missense	Exon 3 of 18	ENSP00000408192.2	Q96KG9-2
	SCYL1	ENST00000524944.5	TSL:1	c.314C>T	p.Ala105Val	missense	Exon 3 of 17	ENSP00000432175.1	E9PS17

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152110 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.0000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000803 AC: 2 AN: 249044 AF XY: 0.00

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 FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000177

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000616 AC: 9 AN: 1461236 Hom.: 0 Cov.: 33 AF XY: 0.00000688 AC XY: 5 AN XY: 726944

African (AFR) AF: 0.00 AC: 0 AN: 33478

American (AMR) AF: 0.00 AC: 0 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52856

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000719 AC: 8 AN: 1111934

Other (OTH) AF: 0.00 AC: 0 AN: 60386

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152110 Hom.: 0 Cov.: 31 AF XY: 0.0000135 AC XY: 1 AN XY: 74296

African (AFR) AF: 0.00 AC: 0 AN: 41404

American (AMR) AF: 0.00 AC: 0 AN: 15264

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5192

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10602

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68030

Other (OTH) AF: 0.00 AC: 0 AN: 2094

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
2	-	-	Acute infantile liver failure-cerebellar ataxia-peripheral sensory motor neuropathy syndrome (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.090
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Benign	-0.45
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Benign	0.074	T
Eigen	Benign	-0.68
Eigen_PC	Benign	-0.68
FATHMM_MKL	Benign	0.10	N
LIST_S2	Benign	0.74	T
M_CAP	Benign	0.013	T
MetaRNN	Benign	0.11	T
MetaSVM	Benign	-0.96	T
PhyloP100		0.97
PrimateAI	Benign	0.37	T
PROVEAN	Benign	-1.0	N
REVEL	Benign	0.061
Sift	Benign	0.23	T
Sift4G	Benign	0.28	T
Polyphen		0.19	B
Vest4		0.24
MutPred		0.23		Gain of methylation at K104 (P = 0.0485)
MVP		0.45
MPC		0.36
ClinPred		0.14	T
GERP RS		0.0051
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.086
gMVP		0.25
Mutation Taster		=0/100	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.96		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.96		Position offset: -2

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

Other links and lift over

dbSNP: rs942522644; hg19: chr11-65293453;