1-36348774-T-G

Variant names:

• chr1-36348774-T-G
• NM_001282547.2:c.665A>C

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_001282547.2(STK40):​c.665A>C​(p.His222Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: STK40 NM_001282547.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.64
• 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 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.874

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
STK40	NM_001282547.2	c.665A>C	p.His222Pro	missense_variant	Exon 7 of 11	ENST00000373132.4	NP_001269476.1
STK40	NM_001282546.2	c.680A>C	p.His227Pro	missense_variant	Exon 7 of 11		NP_001269475.1
STK40	NM_032017.3	c.665A>C	p.His222Pro	missense_variant	Exon 8 of 12		NP_114406.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
STK40	ENST00000373132.4	c.665A>C	p.His222Pro	missense_variant	Exon 7 of 11	1	NM_001282547.2	ENSP00000362224.4
STK40	ENST00000373130.7	c.680A>C	p.His227Pro	missense_variant	Exon 7 of 11	1		ENSP00000362222.3
STK40	ENST00000373129.7	c.665A>C	p.His222Pro	missense_variant	Exon 8 of 12	1		ENSP00000362221.3
STK40	ENST00000359297.6	c.665A>C	p.His222Pro	missense_variant	Exon 6 of 9	2		ENSP00000352245.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jan 23, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.665A>C (p.H222P) alteration is located in exon 8 (coding exon 6) of the STK40 gene. This alteration results from a A to C substitution at nucleotide position 665, causing the histidine (H) at amino acid position 222 to be replaced by a proline (P). 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	0.97
BayesDel_addAF	Pathogenic	0.33	D
BayesDel_noAF	Pathogenic	0.24
CADD	Pathogenic	29
DANN	Uncertain	0.99
DEOGEN2	Benign	0.18	.;T;.;T
Eigen	Pathogenic	0.71
Eigen_PC	Pathogenic	0.69
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.95	D;.;D;D
M_CAP	Uncertain	0.091	D
MetaRNN	Pathogenic	0.87	D;D;D;D
MetaSVM	Uncertain	-0.28	T
MutationAssessor	Benign	1.8	L;L;.;L
PhyloP100		7.6
PrimateAI	Pathogenic	0.89	D
PROVEAN	Pathogenic	-6.3	D;D;D;D
REVEL	Pathogenic	0.72
Sift	Benign	0.032	D;D;D;D
Sift4G	Uncertain	0.0080	D;D;D;D
Polyphen		1.0	D;D;D;D
Vest4		0.94
MutPred		0.57		Gain of methylation at K221 (P = 0.1087);Gain of methylation at K221 (P = 0.1087);.;Gain of methylation at K221 (P = 0.1087);
MVP		0.71
MPC		1.5
ClinPred		0.99	D
GERP RS		5.1
Varity_R		0.97
gMVP		0.95
Mutation Taster		=35/65	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

hg19: chr1-36814375;