Genetic Variant STK40:p.Ala386Pro (chr1-36341907-C-G) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_001282547.2(STK40):c.1156G>C(p.Ala386Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,461,662 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000027 ( 0 hom. )

Consequence

STK40
NM_001282547.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.49

Publications

0 publications found

Variant links:

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]

STK40 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
STK40	NM_001282547.2 link	c.1156G>C	p.Ala386Pro	missense_variant	Exon 11 of 11	ENST00000373132.4	NP_001269476.1	Q8N2I9-1
STK40	NM_001282546.2 link	c.1171G>C	p.Ala391Pro	missense_variant	Exon 11 of 11		NP_001269475.1	Q8N2I9-4
STK40	NM_032017.3 link	c.1156G>C	p.Ala386Pro	missense_variant	Exon 12 of 12		NP_114406.1	Q8N2I9-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
STK40	ENST00000373132.4 link	c.1156G>C	p.Ala386Pro	missense_variant	Exon 11 of 11	1	NM_001282547.2	ENSP00000362224.4	Q8N2I9-1
STK40	ENST00000373130.7 link	c.1171G>C	p.Ala391Pro	missense_variant	Exon 11 of 11	1		ENSP00000362222.3	Q8N2I9-4
STK40	ENST00000373129.7 link	c.1156G>C	p.Ala386Pro	missense_variant	Exon 12 of 12	1		ENSP00000362221.3	Q8N2I9-1
STK40	ENST00000359297.6 link	c.*1292G>C		3_prime_UTR_variant	Exon 9 of 9	2		ENSP00000352245.2	Q8N2I9-3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.0000120

AC:

AN:

249288

AF XY:

0.0000148

show subpopulations

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:

0.0000268

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000274

AC:

AN:

1461662

Hom.:

Cov.:

AF XY:

0.00000413

AC XY:

AN XY:

727148

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33474

American (AMR)

AF:

0.00

AC:

AN:

44716

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26128

East Asian (EAS)

AF:

0.00

AC:

AN:

39694

South Asian (SAS)

AF:

0.00

AC:

AN:

86252

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53358

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5714

European-Non Finnish (NFE)

AF:

0.00000270

AC:

AN:

1111952

Other (OTH)

AF:

0.0000166

AC:

AN:

60374

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.413

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ExAC

AF:

0.0000247

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Feb 22, 2024

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.1156G>C (p.A386P) alteration is located in exon 12 (coding exon 10) of the STK40 gene. This alteration results from a G to C substitution at nucleotide position 1156, causing the alanine (A) at amino acid position 386 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

0.59

BayesDel_addAF

Uncertain

0.11

BayesDel_noAF

Uncertain

-0.020

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.019

T;.;T

Eigen

Benign

-0.0086

Eigen_PC

Benign

0.19

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.94

.;D;D

M_CAP

Benign

0.073

MetaRNN

Uncertain

0.47

T;T;T

MetaSVM

Benign

-0.93

MutationAssessor

Benign

0.90

L;.;L

PhyloP100

7.5

PrimateAI

Pathogenic

0.81

PROVEAN

Benign

-0.18

N;N;N

REVEL

Uncertain

0.31

Sift

Benign

0.32

T;T;T

Sift4G

Benign

0.30

T;T;T

Polyphen

0.0

B;B;B

Vest4

0.70

MutPred

0.40

Gain of glycosylation at A386 (P = 0.0181);.;Gain of glycosylation at A386 (P = 0.0181);

MVP

0.59

MPC

0.48

ClinPred

0.29

GERP RS

5.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.25

gMVP

0.57

Mutation Taster

=18/82

disease causing

(source)

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over