NM_001282547.2:c.868G>A

Variant names:

• chr1-36344136-C-T
• rs199920883
• NM_001282547.2:c.868G>A

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_001282547.2(STK40):​c.868G>A​(p.Glu290Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000578 in 1,609,856 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00011 (0 hom., cov: 30)
  • Exomes 𝑓: 0.000052 (0 hom.)
• Consequence: STK40 NM_001282547.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.45
• Publications: 4 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: Likely_benign. The variant received -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.14350435).
• BS2: High AC in GnomAd4 at 17 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
STK40	NM_001282547.2	c.868G>A	p.Glu290Lys	missense_variant	Exon 8 of 11	ENST00000373132.4	NP_001269476.1
STK40	NM_001282546.2	c.883G>A	p.Glu295Lys	missense_variant	Exon 8 of 11		NP_001269475.1
STK40	NM_032017.3	c.868G>A	p.Glu290Lys	missense_variant	Exon 9 of 12		NP_114406.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
STK40	ENST00000373132.4	c.868G>A	p.Glu290Lys	missense_variant	Exon 8 of 11	1	NM_001282547.2	ENSP00000362224.4
STK40	ENST00000373130.7	c.883G>A	p.Glu295Lys	missense_variant	Exon 8 of 11	1		ENSP00000362222.3
STK40	ENST00000373129.7	c.868G>A	p.Glu290Lys	missense_variant	Exon 9 of 12	1		ENSP00000362221.3
STK40	ENST00000359297.6	c.868G>A	p.Glu290Lys	missense_variant	Exon 7 of 9	2		ENSP00000352245.2

Frequencies

GnomAD3 genomes AF: 0.000113 AC: 17 AN: 150792 Hom.: 0 Cov.: 30

Gnomad AFR AF: 0.0000245

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00202

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000761

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.000485

GnomAD2 exomes AF: 0.000141 AC: 35 AN: 248644 AF XY: 0.000119

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00183

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000562

Gnomad NFE exome AF: 0.0000267

Gnomad OTH exome AF: 0.000166

GnomAD4 exome AF: 0.0000521 AC: 76 AN: 1458946 Hom.: 0 Cov.: 36 AF XY: 0.0000537 AC XY: 39 AN XY: 725716

African (AFR) AF: 0.0000299 AC: 1 AN: 33432

American (AMR) AF: 0.00 AC: 0 AN: 44418

Ashkenazi Jewish (ASJ) AF: 0.00151 AC: 39 AN: 25872

East Asian (EAS) AF: 0.00 AC: 0 AN: 39680

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 85922

European-Finnish (FIN) AF: 0.000263 AC: 14 AN: 53160

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5754

European-Non Finnish (NFE) AF: 0.0000108 AC: 12 AN: 1110426

Other (OTH) AF: 0.000149 AC: 9 AN: 60282

GnomAD4 genome AF: 0.000113 AC: 17 AN: 150910 Hom.: 0 Cov.: 30 AF XY: 0.000149 AC XY: 11 AN XY: 73708

African (AFR) AF: 0.0000244 AC: 1 AN: 41016

American (AMR) AF: 0.00 AC: 0 AN: 15148

Ashkenazi Jewish (ASJ) AF: 0.00202 AC: 7 AN: 3462

East Asian (EAS) AF: 0.00 AC: 0 AN: 5110

South Asian (SAS) AF: 0.00 AC: 0 AN: 4724

European-Finnish (FIN) AF: 0.000761 AC: 8 AN: 10508

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67656

Other (OTH) AF: 0.000480 AC: 1 AN: 2082

Alfa AF: 0.0000908 Hom.: 0

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.000107 AC: 13

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Oct 21, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.868G>A (p.E290K) 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 868, causing the glutamic acid (E) at amino acid position 290 to be replaced by a lysine (K). 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	0.89
BayesDel_addAF	Uncertain	0.090	D
BayesDel_noAF	Uncertain	-0.010
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Benign	0.048	.;T;.;T
Eigen	Uncertain	0.22
Eigen_PC	Uncertain	0.34
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Pathogenic	0.98	D;.;D;D
M_CAP	Uncertain	0.10	D
MetaRNN	Benign	0.14	T;T;T;T
MetaSVM	Benign	-0.88	T
MutationAssessor	Benign	1.2	L;L;.;L
PhyloP100		7.5
PrimateAI	Pathogenic	0.92	D
PROVEAN	Benign	-1.6	N;N;N;N
REVEL	Benign	0.26
Sift	Benign	0.44	T;T;T;T
Sift4G	Benign	0.12	T;T;T;T
Polyphen		0.95	P;D;P;D
Vest4		0.88
MVP		0.36
MPC		0.85
ClinPred		0.41	T
GERP RS		5.4
Varity_R		0.61
gMVP		0.89
Mutation Taster		=47/53	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs199920883; hg19: chr1-36809737; COSMIC: COSV63735658;