1-36344261-C-T

Position:

• chr1-36344261-C-T

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BS2

The NM_001282547.2(STK40):​c.743G>A​(p.Arg248Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000484 in 1,446,680 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000048 (0 hom.)
• Consequence: STK40 NM_001282547.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.48

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

Verdict is Likely_benign. Variant got -4 ACMG points.

• BS2: High AC in GnomAdExome4 at 7 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
STK40	NM_001282547.2	c.743G>A	p.Arg248Gln	missense_variant	8/11	ENST00000373132.4	NP_001269476.1
STK40	NM_001282546.2	c.758G>A	p.Arg253Gln	missense_variant	8/11		NP_001269475.1
STK40	NM_032017.3	c.743G>A	p.Arg248Gln	missense_variant	9/12		NP_114406.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
STK40	ENST00000373132.4	c.743G>A	p.Arg248Gln	missense_variant	8/11	1	NM_001282547.2	ENSP00000362224.4
STK40	ENST00000373130.7	c.758G>A	p.Arg253Gln	missense_variant	8/11	1		ENSP00000362222.3
STK40	ENST00000373129.7	c.743G>A	p.Arg248Gln	missense_variant	9/12	1		ENSP00000362221.3
STK40	ENST00000359297.6	c.743G>A	p.Arg248Gln	missense_variant	7/9	2		ENSP00000352245.2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000484 AC: 7 AN: 1446680 Hom.: 0 Cov.: 35 AF XY: 0.00000417 AC XY: 3 AN XY: 718568

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000228

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0000119

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000272

Gnomad4 OTH exome AF: 0.0000167

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 09, 2023

The c.743G>A (p.R248Q) alteration is located in exon 9 (coding exon 7) of the STK40 gene. This alteration results from a G to A substitution at nucleotide position 743, causing the arginine (R) at amino acid position 248 to be replaced by a glutamine (Q). 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	Benign	0.18
BayesDel_addAF	Uncertain	0.14	D
BayesDel_noAF	Uncertain	-0.040
CADD	Pathogenic	26
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.035	.;T;.;T
Eigen	Uncertain	0.39
Eigen_PC	Uncertain	0.47
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.98	D;.;D;D
M_CAP	Benign	0.074	D
MetaRNN	Uncertain	0.65	D;D;D;D
MetaSVM	Benign	-0.42	T
MutationAssessor	Benign	0.56	N;N;.;N
PrimateAI	Pathogenic	0.83	D
PROVEAN	Benign	-1.3	N;N;N;N
REVEL	Uncertain	0.39
Sift	Benign	0.14	T;T;T;T
Sift4G	Benign	0.19	T;T;T;T
Polyphen		0.98	D;D;D;D
Vest4		0.74
MutPred		0.51		Gain of ubiquitination at K253 (P = 0.0704);Gain of ubiquitination at K253 (P = 0.0704);.;Gain of ubiquitination at K253 (P = 0.0704);
MVP		0.54
MPC		0.89
ClinPred		0.85	D
GERP RS		5.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.48
gMVP		0.75

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		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: rs949864906; hg19: chr1-36809862;