rs1863703

Positions:

• chr2-218679665-A-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_015690.5(STK36):​c.884A>G​(p.Lys295Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.071 in 1,614,022 control chromosomes in the GnomAD database, including 7,694 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.14 (2851 hom., cov: 32)
  • Exomes 𝑓: 0.064 (4843 hom.)
• Consequence: STK36 NM_015690.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.88

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 Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0037926435).
• BP6: Variant 2-218679665-A-G is Benign according to our data. Variant chr2-218679665-A-G is described in ClinVar as [Benign]. Clinvar id is 1280618.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.353 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
STK36	NM_015690.5	c.884A>G	p.Lys295Arg	missense_variant	8/27	ENST00000295709.8	NP_056505.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
STK36	ENST00000295709.8	c.884A>G	p.Lys295Arg	missense_variant	8/27	1	NM_015690.5	ENSP00000295709.3
STK36	ENST00000392105.7	c.884A>G	p.Lys295Arg	missense_variant	8/27	1		ENSP00000375954.3
STK36	ENST00000440309.5	c.884A>G	p.Lys295Arg	missense_variant	8/27	5		ENSP00000394095.1
STK36	ENST00000424080.1	c.*48A>G		downstream_gene_variant		5		ENSP00000403527.1

Frequencies

GnomAD3 genomes AF: 0.141 AC: 21481 AN: 152018 Hom.: 2839 Cov.: 32

Gnomad AFR AF: 0.357

Gnomad AMI AF: 0.0263

Gnomad AMR AF: 0.0838

Gnomad ASJ AF: 0.0634

Gnomad EAS AF: 0.0764

Gnomad SAS AF: 0.0552

Gnomad FIN AF: 0.0374

Gnomad MID AF: 0.149

Gnomad NFE AF: 0.0561

Gnomad OTH AF: 0.136

GnomAD3 exomes AF: 0.0779 AC: 19566 AN: 251286 Hom.: 1514 AF XY: 0.0723 AC XY: 9812 AN XY: 135806

Gnomad AFR exome AF: 0.369

Gnomad AMR exome AF: 0.0510

Gnomad ASJ exome AF: 0.0617

Gnomad EAS exome AF: 0.0769

Gnomad SAS exome AF: 0.0563

Gnomad FIN exome AF: 0.0443

Gnomad NFE exome AF: 0.0583

Gnomad OTH exome AF: 0.0763

GnomAD4 exome AF: 0.0636 AC: 93010 AN: 1461886 Hom.: 4843 Cov.: 32 AF XY: 0.0628 AC XY: 45665 AN XY: 727246

Gnomad4 AFR exome AF: 0.377

Gnomad4 AMR exome AF: 0.0534

Gnomad4 ASJ exome AF: 0.0646

Gnomad4 EAS exome AF: 0.0664

Gnomad4 SAS exome AF: 0.0566

Gnomad4 FIN exome AF: 0.0444

Gnomad4 NFE exome AF: 0.0546

Gnomad4 OTH exome AF: 0.0843

GnomAD4 genome AF: 0.142 AC: 21544 AN: 152136 Hom.: 2851 Cov.: 32 AF XY: 0.137 AC XY: 10160 AN XY: 74398

Gnomad4 AFR AF: 0.357

Gnomad4 AMR AF: 0.0838

Gnomad4 ASJ AF: 0.0634

Gnomad4 EAS AF: 0.0766

Gnomad4 SAS AF: 0.0557

Gnomad4 FIN AF: 0.0374

Gnomad4 NFE AF: 0.0561

Gnomad4 OTH AF: 0.136

Alfa AF: 0.0728 Hom.: 1758

Bravo AF: 0.155

TwinsUK AF: 0.0566 AC: 210

ALSPAC AF: 0.0618 AC: 238

ESP6500AA AF: 0.351 AC: 1548

ESP6500EA AF: 0.0565 AC: 486

ExAC AF: 0.0847 AC: 10282

Asia WGS AF: 0.0860 AC: 297 AN: 3478

EpiCase AF: 0.0620

EpiControl AF: 0.0649

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	May 05, 2021	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.072
BayesDel_addAF	Benign	-0.57	T
BayesDel_noAF	Benign	-0.44
CADD	Benign	16
DANN	Benign	0.97
DEOGEN2	Benign	0.10	T;.;T
Eigen	Benign	-0.36
Eigen_PC	Benign	-0.20
FATHMM_MKL	Benign	0.60	D
LIST_S2	Benign	0.78	.;T;T
MetaRNN	Benign	0.0038	T;T;T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	1.9	L;L;L
PrimateAI	Benign	0.35	T
PROVEAN	Benign	-0.18	N;N;N
REVEL	Benign	0.035
Sift	Benign	0.44	T;T;T
Sift4G	Benign	0.66	T;T;T
Polyphen		0.056	B;B;B
Vest4		0.066
MPC		0.14
ClinPred		0.014	T
GERP RS		3.0
Varity_R		0.029
gMVP		0.24

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

LitVar

Other links and lift over

dbSNP: rs1863703; hg19: chr2-219544388; COSMIC: COSV99831077; COSMIC: COSV99831077;