19-1226556-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 0P and 11B. BP4_ModerateBP6BS1BS2

The NM_000455.5(STK11):c.1211C>T(p.Ser404Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000776 in 1,599,480 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S404Y) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00051 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00080 ( 1 hom. )

Consequence

STK11
NM_000455.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:6B:24

Conservation

PhyloP100: 1.47

Publications

18 publications found

Variant links:

COSMIC-nc: COSV99289465

Genes affected

STK11 (HGNC:11389): (serine/threonine kinase 11) The protein encoded by this gene is a serine/threonine kinase that regulates cell polarity and energy metabolism and functions as a tumor suppressor. Mutations in this gene have been associated with the autosomal dominant Peutz-Jeghers syndrome, as well as with skin, pancreatic, and testicular cancers. [provided by RefSeq, May 2022]

STK11 Gene-Disease associations (from GenCC):

familial pancreatic carcinoma
Inheritance: AD Classification: DEFINITIVE Submitted by: G2P
Peutz-Jeghers syndrome
Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: ClinGen, Labcorp Genetics (formerly Invitae), G2P, Genomics England PanelApp, Orphanet
familial ovarian cancer
Inheritance: Unknown Classification: NO_KNOWN Submitted by: ClinGen

STK11 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -11 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0695084).

BP6

Variant 19-1226556-C-T is Benign according to our data. Variant chr19-1226556-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 127700.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.000505 (77/152368) while in subpopulation NFE AF = 0.000867 (59/68030). AF 95% confidence interval is 0.00069. There are 0 homozygotes in GnomAd4. There are 28 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High AC in GnomAd4 at 77 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000455.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	STK11	NM_000455.5	MANE Select	c.1211C>T	p.Ser404Phe	missense	Exon 9 of 10	NP_000446.1	A0A0S2Z4D1
	STK11	NR_176325.1		n.2478C>T		non_coding_transcript_exon	Exon 10 of 11

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
STK11	ENST00000326873.12	TSL:1 MANE Select	c.1211C>T	p.Ser404Phe	missense	Exon 9 of 10	ENSP00000324856.6	Q15831-1
STK11	ENST00000585748.3	TSL:3	c.839C>T	p.Ser280Phe	missense	Exon 11 of 12	ENSP00000477641.2	A0A087WT72
STK11	ENST00000593219.6	TSL:3	n.*1036C>T		non_coding_transcript_exon	Exon 10 of 11	ENSP00000466610.1	K7EMR0

Frequencies

GnomAD3 genomes

AF:

0.000506

AC:

AN:

152250

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000392

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000867

Gnomad OTH

AF:

0.000956

GnomAD2 exomes

AF:

0.000471

AC:

103

AN:

218818

AF XY:

0.000432

show subpopulations

Gnomad AFR exome

AF:

0.0000829

Gnomad AMR exome

AF:

0.000249

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000890

Gnomad OTH exome

AF:

0.000916

GnomAD4 exome

AF:

0.000804

AC:

1164

AN:

1447112

Hom.:

Cov.:

AF XY:

0.000779

AC XY:

560

AN XY:

718696

show subpopulations

African (AFR)

AF:

0.000211

AC:

AN:

33164

American (AMR)

AF:

0.000372

AC:

AN:

42960

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25790

East Asian (EAS)

AF:

0.00

AC:

AN:

38890

South Asian (SAS)

AF:

0.000107

AC:

AN:

83980

European-Finnish (FIN)

AF:

0.00

AC:

AN:

50600

Middle Eastern (MID)

AF:

0.00159

AC:

AN:

5648

European-Non Finnish (NFE)

AF:

0.000984

AC:

1089

AN:

1106374

Other (OTH)

AF:

0.000569

AC:

AN:

59706

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.488

Heterozygous variant carriers

164

247

329

411

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

126

168

210

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000505

AC:

AN:

152368

Hom.:

Cov.:

AF XY:

0.000376

AC XY:

AN XY:

74502

show subpopulations

African (AFR)

AF:

0.000240

AC:

AN:

41586

American (AMR)

AF:

0.000392

AC:

AN:

15308

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5194

South Asian (SAS)

AF:

0.00

AC:

AN:

4834

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10628

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000867

AC:

AN:

68030

Other (OTH)

AF:

0.000946

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.507

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00104

Hom.:

Bravo

AF:

0.000578

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000611

AC:

ExAC

AF:

0.000479

AC:

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (8)

not specified (7)

Peutz-Jeghers syndrome (7)

Hereditary cancer-predisposing syndrome (4)

Breast and/or ovarian cancer (1)

Hereditary breast ovarian cancer syndrome (1)

Malignant tumor of breast (1)

STK11-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.44

BayesDel_noAF

Benign

-0.49

CADD

Benign

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.33

Eigen

Benign

-0.63

Eigen_PC

Benign

-0.66

FATHMM_MKL

Benign

0.12

LIST_S2

Benign

0.74

M_CAP

Uncertain

0.28

MetaRNN

Benign

0.070

MetaSVM

Benign

-0.84

MutationAssessor

Benign

1.5

PhyloP100

1.5

PrimateAI

Benign

0.37

PROVEAN

Benign

-1.8

REVEL

Uncertain

0.63

Sift

Benign

0.044

Sift4G

Uncertain

0.043

Polyphen

0.055

Vest4

0.77

MVP

0.42

MPC

0.047

ClinPred

0.028

GERP RS

2.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.059

gMVP

0.16

Mutation Taster

=29/71

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over