rs1344642

Positions:

• chr2-218690539-G-A
• chr2-218690539-G-T

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.1748G>A​(p.Arg583Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.437 in 1,612,946 control chromosomes in the GnomAD database, including 159,073 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 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. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R583W) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.48 (18802 hom., cov: 32)
  • Exomes 𝑓: 0.43 (140271 hom.)
• Consequence: STK36 NM_015690.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.78

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=3.5153664E-6).
• BP6: Variant 2-218690539-G-A is Benign according to our data. Variant chr2-218690539-G-A is described in ClinVar as [Benign]. Clinvar id is 403497.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.638 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
STK36	NM_015690.5	c.1748G>A	p.Arg583Gln	missense_variant	14/27	ENST00000295709.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
STK36	ENST00000295709.8	c.1748G>A	p.Arg583Gln	missense_variant	14/27	1	NM_015690.5	P1

Frequencies

GnomAD3 genomes AF: 0.482 AC: 73247 AN: 151902 Hom.: 18751 Cov.: 32

Gnomad AFR AF: 0.643

Gnomad AMI AF: 0.350

Gnomad AMR AF: 0.443

Gnomad ASJ AF: 0.415

Gnomad EAS AF: 0.138

Gnomad SAS AF: 0.327

Gnomad FIN AF: 0.437

Gnomad MID AF: 0.404

Gnomad NFE AF: 0.444

Gnomad OTH AF: 0.457

GnomAD3 exomes AF: 0.413 AC: 103838 AN: 251210 Hom.: 22959 AF XY: 0.409 AC XY: 55487 AN XY: 135778

Gnomad AFR exome AF: 0.653

Gnomad AMR exome AF: 0.402

Gnomad ASJ exome AF: 0.405

Gnomad EAS exome AF: 0.137

Gnomad SAS exome AF: 0.337

Gnomad FIN exome AF: 0.445

Gnomad NFE exome AF: 0.441

Gnomad OTH exome AF: 0.434

GnomAD4 exome AF: 0.432 AC: 631525 AN: 1460926 Hom.: 140271 Cov.: 37 AF XY: 0.428 AC XY: 311188 AN XY: 726824

Gnomad4 AFR exome AF: 0.658

Gnomad4 AMR exome AF: 0.406

Gnomad4 ASJ exome AF: 0.410

Gnomad4 EAS exome AF: 0.129

Gnomad4 SAS exome AF: 0.337

Gnomad4 FIN exome AF: 0.441

Gnomad4 NFE exome AF: 0.445

Gnomad4 OTH exome AF: 0.434

GnomAD4 genome AF: 0.483 AC: 73359 AN: 152020 Hom.: 18802 Cov.: 32 AF XY: 0.475 AC XY: 35284 AN XY: 74308

Gnomad4 AFR AF: 0.644

Gnomad4 AMR AF: 0.443

Gnomad4 ASJ AF: 0.415

Gnomad4 EAS AF: 0.139

Gnomad4 SAS AF: 0.328

Gnomad4 FIN AF: 0.437

Gnomad4 NFE AF: 0.444

Gnomad4 OTH AF: 0.457

Alfa AF: 0.438 Hom.: 36217

Bravo AF: 0.492

TwinsUK AF: 0.444 AC: 1645

ALSPAC AF: 0.445 AC: 1714

ESP6500AA AF: 0.636 AC: 2804

ESP6500EA AF: 0.439 AC: 3775

ExAC AF: 0.419 AC: 50909

Asia WGS AF: 0.281 AC: 980 AN: 3478

EpiCase AF: 0.442

EpiControl AF: 0.444

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Mar 29, 2016

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

May 04, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.068
BayesDel_addAF	Benign	-0.58	T
BayesDel_noAF	Benign	-0.46
CADD	Benign	17
DANN	Uncertain	0.98
DEOGEN2	Benign	0.13	T;.;T
Eigen	Benign	-0.86
Eigen_PC	Benign	-0.79
FATHMM_MKL	Benign	0.20	N
MetaRNN	Benign	0.0000035	T;T;T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	0.26	N;N;N
MutationTaster	Benign	1.0	P;P;P;P
PrimateAI	Benign	0.24	T
PROVEAN	Benign	-0.74	N;N;N
REVEL	Benign	0.025
Sift	Benign	0.13	T;T;T
Sift4G	Benign	0.54	T;T;T
Polyphen		0.041	B;B;B
Vest4		0.087
MPC		0.20
ClinPred		0.0017	T
GERP RS		2.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.039
gMVP		0.31

Splicing

Name	Calibrated prediction	Score	Prediction
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: rs1344642; hg19: chr2-219555262; COSMIC: COSV55325134; COSMIC: COSV55325134;