1-36343912-G-A

Variant names:

• chr1-36343912-G-A
• rs1200783623
• NM_001282547.2:c.952C>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 4P and 4B. PP3_Strong BS2

The NM_001282547.2(STK40):​c.952C>T​(p.Arg318Cys) variant causes a missense change. The variant allele was found at a frequency of 0.0000055 in 1,454,998 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 13/22 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000055 (0 hom.)
• Consequence: STK40 NM_001282547.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.79
• Publications: 0 publications found

Genes affected

STK40 (HGNC:21373): (serine/threonine kinase 40) Predicted to enable ATP binding activity; protein serine kinase activity; and protein serine/threonine kinase activity. Predicted to be involved in protein phosphorylation. Predicted to act upstream of or within several processes, including glycogen metabolic process; lung development; and respiratory system process. Located in cytosol and nucleoplasm. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PP3: MetaRNN computational evidence supports a deleterious effect, 0.987
• BS2: High AC in GnomAdExome4 at 8 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
STK40	NM_001282547.2	c.952C>T	p.Arg318Cys	missense_variant	Exon 9 of 11	ENST00000373132.4	NP_001269476.1
STK40	NM_001282546.2	c.967C>T	p.Arg323Cys	missense_variant	Exon 9 of 11		NP_001269475.1
STK40	NM_032017.3	c.952C>T	p.Arg318Cys	missense_variant	Exon 10 of 12		NP_114406.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
STK40	ENST00000373132.4	c.952C>T	p.Arg318Cys	missense_variant	Exon 9 of 11	1	NM_001282547.2	ENSP00000362224.4
STK40	ENST00000373130.7	c.967C>T	p.Arg323Cys	missense_variant	Exon 9 of 11	1		ENSP00000362222.3
STK40	ENST00000373129.7	c.952C>T	p.Arg318Cys	missense_variant	Exon 10 of 12	1		ENSP00000362221.3
STK40	ENST00000359297.6	c.952C>T	p.Arg318Cys	missense_variant	Exon 8 of 9	2		ENSP00000352245.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00000403 AC: 1 AN: 247950 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000892

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000550 AC: 8 AN: 1454998 Hom.: 0 Cov.: 31 AF XY: 0.00000554 AC XY: 4 AN XY: 722512

African (AFR) AF: 0.0000300 AC: 1 AN: 33362

American (AMR) AF: 0.00 AC: 0 AN: 44230

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26046

East Asian (EAS) AF: 0.00 AC: 0 AN: 39512

South Asian (SAS) AF: 0.00 AC: 0 AN: 86036

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52972

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5744

European-Non Finnish (NFE) AF: 0.00000632 AC: 7 AN: 1107098

Other (OTH) AF: 0.00 AC: 0 AN: 59998

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Dec 11, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.952C>T (p.R318C) alteration is located in exon 10 (coding exon 8) of the STK40 gene. This alteration results from a C to T substitution at nucleotide position 952, causing the arginine (R) at amino acid position 318 to be replaced by a cysteine (C). 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	1.0
BayesDel_addAF	Pathogenic	0.52	D
BayesDel_noAF	Pathogenic	0.50
CADD	Pathogenic	34
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.43	.;T;.;T
Eigen	Pathogenic	0.97
Eigen_PC	Pathogenic	0.84
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.92	D;.;D;D
M_CAP	Pathogenic	0.64	D
MetaRNN	Pathogenic	0.99	D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	5.0	H;H;.;H
PhyloP100		5.8
PrimateAI	Pathogenic	0.81	D
PROVEAN	Pathogenic	-7.1	D;D;D;D
REVEL	Pathogenic	0.94
Sift	Uncertain	0.0050	D;D;D;D
Sift4G	Pathogenic	0.0	D;D;D;D
Polyphen		1.0	D;D;D;D
Vest4		0.94
MutPred		0.92		Gain of catalytic residue at L319 (P = 0.0203);Gain of catalytic residue at L319 (P = 0.0203);.;Gain of catalytic residue at L319 (P = 0.0203);
MVP		0.83
MPC		1.4
ClinPred		1.0	D
GERP RS		5.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.9
Varity_R		0.87
gMVP		0.97
Mutation Taster		=31/69	disease causing

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

Other links and lift over

dbSNP: rs1200783623; hg19: chr1-36809513;