2-218697952-G-A

Position:

• chr2-218697952-G-A

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.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. 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 0.28 (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

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -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 id 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
STK36	NM_015690.5	c.3008G>A	p.Gly1003Asp	missense_variant	25/27	ENST00000295709.8	NP_056505.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
STK36	ENST00000295709.8	c.3008G>A	p.Gly1003Asp	missense_variant	25/27	1	NM_015690.5	ENSP00000295709.3

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

GnomAD3 exomes AF: 0.319 AC: 80264 AN: 251388 Hom.: 14424 AF XY: 0.325 AC XY: 44094 AN XY: 135866

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 SAS exome AF: 0.280

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

Gnomad4 AFR exome AF: 0.0591

Gnomad4 AMR exome AF: 0.341

Gnomad4 ASJ exome AF: 0.346

Gnomad4 EAS exome AF: 0.0629

Gnomad4 SAS exome AF: 0.279

Gnomad4 FIN exome AF: 0.397

Gnomad4 NFE exome AF: 0.390

Gnomad4 OTH exome AF: 0.334

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

Gnomad4 AFR AF: 0.0693

Gnomad4 AMR AF: 0.333

Gnomad4 ASJ AF: 0.351

Gnomad4 EAS AF: 0.0622

Gnomad4 SAS AF: 0.271

Gnomad4 FIN AF: 0.399

Gnomad4 NFE AF: 0.387

Gnomad4 OTH AF: 0.281

Alfa AF: 0.358 Hom.: 25947

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

Significance: Benign

Submissions summary: Benign:3

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	Feb 06, 2020	- -

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 -

Computational scores

Source: dbNSFP v4.3

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;.;T
Eigen	Benign	-0.87
Eigen_PC	Benign	-0.93
FATHMM_MKL	Benign	0.064	N
LIST_S2	Benign	0.57	.;T;T
MetaRNN	Benign	0.0013	T;T;T
MetaSVM	Benign	-0.91	T
MutationAssessor	Benign	2.0	M;.;M
PrimateAI	Benign	0.29	T
PROVEAN	Benign	-0.45	N;N;N
REVEL	Benign	0.18
Sift	Benign	0.52	T;T;T
Sift4G	Benign	0.62	T;T;T
Polyphen		0.18	B;P;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

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

Publications

LitVar

Other links and lift over

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