rs1863704

Variant names:

• chr2-218697952-G-A
• rs1863704
• NM_015690.5:c.3008G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_015690.5(STK36):​c.3008G>A​(p.Gly1003Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.354 in 1,613,918 control chromosomes in the GnomAD database, including 108,220 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.28 (7488 hom., cov: 32)
  • Exomes 𝑓: 0.36 (100732 hom.)
• Consequence: STK36 NM_015690.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.900
• Publications: 62 publications found

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]

STK36 Gene-Disease associations (from GenCC):

• ciliary dyskinesia, primary, 46

  Inheritance: AR Classification: MODERATE, LIMITED Submitted by: PanelApp Australia, Labcorp Genetics (formerly Invitae), ClinGen, Ambry Genetics
• primary ciliary dyskinesia

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0013133585).
• BP6: Variant 2-218697952-G-A is Benign according to our data. Variant chr2-218697952-G-A is described in ClinVar as Benign. ClinVar VariationId is 403498.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.383 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_015690.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	STK36	NM_015690.5	MANE Select	c.3008G>A	p.Gly1003Asp	missense	Exon 25 of 27	NP_056505.2	Q9NRP7-1
	STK36	NM_001369423.1		c.3008G>A	p.Gly1003Asp	missense	Exon 25 of 27	NP_001356352.1	Q9NRP7-1
	STK36	NM_001243313.2		c.2945G>A	p.Gly982Asp	missense	Exon 25 of 27	NP_001230242.1	Q9NRP7-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	STK36	ENST00000295709.8	TSL:1 MANE Select	c.3008G>A	p.Gly1003Asp	missense	Exon 25 of 27	ENSP00000295709.3	Q9NRP7-1
	STK36	ENST00000392105.7	TSL:1	c.2945G>A	p.Gly982Asp	missense	Exon 25 of 27	ENSP00000375954.3	Q9NRP7-2
	STK36	ENST00000440309.5	TSL:5	c.3008G>A	p.Gly1003Asp	missense	Exon 25 of 27	ENSP00000394095.1	Q9NRP7-1

Frequencies

GnomAD3 genomes AF: 0.278 AC: 42250 AN: 151954 Hom.: 7488 Cov.: 32

Gnomad AFR AF: 0.0695

Gnomad AMI AF: 0.325

Gnomad AMR AF: 0.334

Gnomad ASJ AF: 0.351

Gnomad EAS AF: 0.0616

Gnomad SAS AF: 0.270

Gnomad FIN AF: 0.399

Gnomad MID AF: 0.237

Gnomad NFE AF: 0.387

Gnomad OTH AF: 0.279

GnomAD2 exomes AF: 0.319 AC: 80264 AN: 251388 AF XY: 0.325

Gnomad AFR exome AF: 0.0636

Gnomad AMR exome AF: 0.341

Gnomad ASJ exome AF: 0.343

Gnomad EAS exome AF: 0.0606

Gnomad FIN exome AF: 0.401

Gnomad NFE exome AF: 0.382

Gnomad OTH exome AF: 0.351

GnomAD4 exome AF: 0.362 AC: 529721 AN: 1461846 Hom.: 100732 Cov.: 52 AF XY: 0.360 AC XY: 261769 AN XY: 727224

African (AFR) AF: 0.0591 AC: 1979 AN: 33480

American (AMR) AF: 0.341 AC: 15238 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.346 AC: 9033 AN: 26136

East Asian (EAS) AF: 0.0629 AC: 2496 AN: 39700

South Asian (SAS) AF: 0.279 AC: 24099 AN: 86258

European-Finnish (FIN) AF: 0.397 AC: 21198 AN: 53392

Middle Eastern (MID) AF: 0.272 AC: 1569 AN: 5768

European-Non Finnish (NFE) AF: 0.390 AC: 433912 AN: 1111992

Other (OTH) AF: 0.334 AC: 20197 AN: 60396

GnomAD4 genome AF: 0.278 AC: 42249 AN: 152072 Hom.: 7488 Cov.: 32 AF XY: 0.277 AC XY: 20556 AN XY: 74308

African (AFR) AF: 0.0693 AC: 2879 AN: 41520

American (AMR) AF: 0.333 AC: 5084 AN: 15266

Ashkenazi Jewish (ASJ) AF: 0.351 AC: 1219 AN: 3472

East Asian (EAS) AF: 0.0622 AC: 322 AN: 5180

South Asian (SAS) AF: 0.271 AC: 1307 AN: 4826

European-Finnish (FIN) AF: 0.399 AC: 4209 AN: 10546

Middle Eastern (MID) AF: 0.224 AC: 66 AN: 294

European-Non Finnish (NFE) AF: 0.387 AC: 26276 AN: 67950

Other (OTH) AF: 0.281 AC: 592 AN: 2110

Alfa AF: 0.344 Hom.: 33832

Bravo AF: 0.266

TwinsUK AF: 0.387 AC: 1434

ALSPAC AF: 0.382 AC: 1473

ESP6500AA AF: 0.0763 AC: 336

ESP6500EA AF: 0.382 AC: 3284

ExAC AF: 0.315 AC: 38187

Asia WGS AF: 0.178 AC: 621 AN: 3478

EpiCase AF: 0.380

EpiControl AF: 0.378

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.48	T
BayesDel_noAF	Benign	-0.31
CADD	Benign	9.7
DANN	Benign	0.28
DEOGEN2	Benign	0.12	T
Eigen	Benign	-0.87
Eigen_PC	Benign	-0.93
FATHMM_MKL	Benign	0.064	N
LIST_S2	Benign	0.57	T
MetaRNN	Benign	0.0013	T
MetaSVM	Benign	-0.91	T
MutationAssessor	Benign	2.0	M
PhyloP100		0.90
PrimateAI	Benign	0.29	T
PROVEAN	Benign	-0.45	N
REVEL	Benign	0.18
Sift	Benign	0.52	T
Sift4G	Benign	0.62	T
Polyphen		0.18	B
Vest4		0.085
MPC		0.22
ClinPred		0.0022	T
GERP RS		2.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.023
gMVP		0.45
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.11		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs1863704; hg19: chr2-219562675; COSMIC: COSV55325057; COSMIC: COSV55325057;