10-103992985-A-C

Variant summary

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

The NM_014720.4(SLK):c.366A>C(p.Glu122Asp) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/23 in silico tools predict a benign 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: 0.0001473
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.09

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.23426467).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SLK	NM_014720.4	c.366A>C	p.Glu122Asp	missense_variant, splice_region_variant	4/19	ENST00000369755.4
SLK	NM_001304743.2	c.366A>C	p.Glu122Asp	missense_variant, splice_region_variant	4/18
SLK	XM_011540401.4	c.366A>C	p.Glu122Asp	missense_variant, splice_region_variant	4/18
SLK	XM_047426039.1	c.366A>C	p.Glu122Asp	missense_variant, splice_region_variant	4/17

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SLK	ENST00000369755.4	c.366A>C	p.Glu122Asp	missense_variant, splice_region_variant	4/19	1	NM_014720.4	P1
SLK	ENST00000335753.8	c.366A>C	p.Glu122Asp	missense_variant, splice_region_variant	4/18	1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

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

Dec 18, 2023

The c.366A>C (p.E122D) alteration is located in exon 4 (coding exon 4) of the SLK gene. This alteration results from a A to C substitution at nucleotide position 366, causing the glutamic acid (E) at amino acid position 122 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	Pathogenic	0.95
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Benign	-0.51
Cadd	Benign	22
Dann	Uncertain	1.0
Eigen	Benign	-0.064
Eigen_PC	Benign	-0.043
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Uncertain	0.95	D;D
M_CAP	Benign	0.030	D
MetaRNN	Benign	0.23	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.075	N;N
MutationTaster	Benign	1.0	D;D
PrimateAI	Pathogenic	0.79	T
PROVEAN	Uncertain	-2.4	N;N
REVEL	Benign	0.082
Sift	Benign	0.069	T;T
Sift4G	Benign	0.11	T;T
Polyphen		0.95	P;P
Vest4		0.47
MutPred		0.36		Loss of disorder (P = 0.1781);Loss of disorder (P = 0.1781);
MVP		0.29
MPC		1.1
ClinPred		0.92	D
GERP RS		3.0
Varity_R		0.36
gMVP		0.75

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00015
dbscSNV1_RF	Benign	0.068
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

No publications associated with this variant yet.

Other links and lift over

hg19: chr10-105752743;