10-103999312-T-G

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_014720.4(SLK):c.781T>G(p.Trp261Gly) variant causes a missense, splice region 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. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: SLK NM_014720.4 missense, splice_region
• Scores: Splicing: ADA: 0.9419
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 8.02

Genes affected

SLK (HGNC:11088): (STE20 like kinase) Enables protein homodimerization activity and protein serine/threonine kinase activity. Involved in several processes, including cytoplasmic microtubule organization; protein autophosphorylation; and regulation of focal adhesion assembly. Located in perinuclear region of cytoplasm. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.87

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SLK	NM_014720.4	c.781T>G	p.Trp261Gly	missense_variant, splice_region_variant	6/19	ENST00000369755.4
SLK	NM_001304743.2	c.781T>G	p.Trp261Gly	missense_variant, splice_region_variant	6/18
SLK	XM_011540401.4	c.781T>G	p.Trp261Gly	missense_variant, splice_region_variant	6/18
SLK	XM_047426039.1	c.781T>G	p.Trp261Gly	missense_variant, splice_region_variant	6/17

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SLK	ENST00000369755.4	c.781T>G	p.Trp261Gly	missense_variant, splice_region_variant	6/19	1	NM_014720.4	P1
SLK	ENST00000335753.8	c.781T>G	p.Trp261Gly	missense_variant, splice_region_variant	6/18	1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 24, 2023

The c.781T>G (p.W261G) alteration is located in exon 6 (coding exon 6) of the SLK gene. This alteration results from a T to G substitution at nucleotide position 781, causing the tryptophan (W) at amino acid position 261 to be replaced by a glycine (G). 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	0.99
BayesDel_addAF	Pathogenic	0.25	D
BayesDel_noAF	Uncertain	0.12
Cadd	Pathogenic	30
Dann	Benign	0.97
Eigen	Uncertain	0.64
Eigen_PC	Uncertain	0.60
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.93	D;D
M_CAP	Benign	0.053	D
MetaRNN	Pathogenic	0.87	D;D
MetaSVM	Benign	-0.92	T
MutationAssessor	Uncertain	2.4	M;M
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.77	T
PROVEAN	Pathogenic	-12	D;D
REVEL	Pathogenic	0.65
Sift	Uncertain	0.0040	D;D
Sift4G	Uncertain	0.0050	D;D
Polyphen		1.0	D;D
Vest4		0.84
MutPred		0.69		Gain of disorder (P = 0.0137);Gain of disorder (P = 0.0137);
MVP		0.28
MPC		2.6
ClinPred		1.0	D
GERP RS		5.6
Varity_R		0.96
gMVP		0.80

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.94
dbscSNV1_RF	Benign	0.48
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

LitVar

Other links and lift over

dbSNP: rs1250888254; hg19: chr10-105759070;