2-218675404-T-A

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_015690.5(STK36):c.365T>A(p.Leu122Gln) variant causes a missense 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. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L122P) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: STK36 NM_015690.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.98

Genes affected

STK36 (HGNC:17209): (serine/threonine kinase 36) This gene encodes a member of the serine/threonine kinase family of enzymes. This family member is similar to a Drosophila protein that plays a key role in the Hedgehog signaling pathway. This human protein is a positive regulator of the GLI zinc-finger transcription factors. Knockout studies of the homologous mouse gene suggest that defects in this human gene may lead to congenital hydrocephalus, possibly due to a functional defect in motile cilia. Because Hedgehog signaling is frequently activated in certain kinds of gastrointestinal cancers, it has been suggested that this gene is a target for the treatment of these cancers. Alternative splicing of this gene results in multiple transcript variants. [provided by RefSeq, Aug 2011]

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.965

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
STK36	NM_015690.5	c.365T>A	p.Leu122Gln	missense_variant	5/27	ENST00000295709.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
STK36	ENST00000295709.8	c.365T>A	p.Leu122Gln	missense_variant	5/27	1	NM_015690.5	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

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

Feb 02, 2024

The c.365T>A (p.L122Q) alteration is located in exon 5 (coding exon 4) of the STK36 gene. This alteration results from a T to A substitution at nucleotide position 365, causing the leucine (L) at amino acid position 122 to be replaced by a glutamine (Q). 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	0.44	D
BayesDel_noAF	Pathogenic	0.39
Cadd	Pathogenic	30
Dann	Uncertain	1.0
DEOGEN2	Benign	0.39	T;.;.;T;.
Eigen	Pathogenic	0.74
Eigen_PC	Pathogenic	0.72
FATHMM_MKL	Pathogenic	0.99	D
M_CAP	Uncertain	0.16	D
MetaRNN	Pathogenic	0.97	D;D;D;D;D
MetaSVM	Uncertain	0.47	D
MutationAssessor	Uncertain	2.5	M;M;.;M;.
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Pathogenic	0.83	D
PROVEAN	Pathogenic	-5.2	D;D;D;D;D
REVEL	Pathogenic	0.66
Sift	Uncertain	0.0010	D;D;D;D;D
Sift4G	Uncertain	0.0020	D;D;D;D;D
Polyphen		1.0	D;D;.;D;.
Vest4		0.98
MutPred		0.88		Gain of disorder (P = 0.0136);Gain of disorder (P = 0.0136);.;Gain of disorder (P = 0.0136);Gain of disorder (P = 0.0136);
MVP		0.95
MPC		0.72
ClinPred		1.0	D
GERP RS		5.7
Varity_R		0.83
gMVP		0.77

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr2-219540127;