rs59912467

Variant names:

• chr19-1223126-C-G
• rs59912467
• NM_000455.5:c.1062C>G

Your query was ambiguous. Multiple possible variants found:

• chr19-1223126-C-G
• chr19-1223126-C-T
• chr19-1223126-C-A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_000455.5(STK11):​c.1062C>G​(p.Phe354Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0051 in 1,611,676 control chromosomes in the GnomAD database, including 56 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. F354S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0040 (7 hom., cov: 33)
  • Exomes 𝑓: 0.0052 (49 hom.)
• Consequence: STK11 NM_000455.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts U:3 B:31 O:1
• Conservation: PhyloP100: -1.12
• Publications: 163 publications found

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

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.05135572).
• BP6: Variant 19-1223126-C-G is Benign according to our data. Variant chr19-1223126-C-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 7461.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.00396 (602/152154) while in subpopulation EAS AF = 0.0408 (211/5166). AF 95% confidence interval is 0.0363. There are 7 homozygotes in GnomAd4. There are 295 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High AC in GnomAd4 at 602 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.1062C>G	p.Phe354Leu	missense	Exon 8 of 10	NP_000446.1	A0A0S2Z4D1
	STK11	NM_001407255.1		c.1062C>G	p.Phe354Leu	missense	Exon 8 of 9	NP_001394184.1	Q15831-2
	STK11	NR_176325.1		n.2329C>G		non_coding_transcript_exon	Exon 9 of 11

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	STK11	ENST00000326873.12	TSL:1 MANE Select	c.1062C>G	p.Phe354Leu	missense	Exon 8 of 10	ENSP00000324856.6	Q15831-1
	STK11	ENST00000652231.1		c.1062C>G	p.Phe354Leu	missense	Exon 8 of 9	ENSP00000498804.1	Q15831-2
	STK11	ENST00000585748.3	TSL:3	c.690C>G	p.Phe230Leu	missense	Exon 10 of 12	ENSP00000477641.2	A0A087WT72

Frequencies

GnomAD3 genomes AF: 0.00396 AC: 602 AN: 152036 Hom.: 7 Cov.: 33

Gnomad AFR AF: 0.000967

Gnomad AMI AF: 0.00220

Gnomad AMR AF: 0.00262

Gnomad ASJ AF: 0.00721

Gnomad EAS AF: 0.0407

Gnomad SAS AF: 0.00624

Gnomad FIN AF: 0.000283

Gnomad MID AF: 0.00637

Gnomad NFE AF: 0.00359

Gnomad OTH AF: 0.00240

GnomAD2 exomes AF: 0.00520 AC: 1274 AN: 245022 AF XY: 0.00519

Gnomad AFR exome AF: 0.000930

Gnomad AMR exome AF: 0.00125

Gnomad ASJ exome AF: 0.00614

Gnomad EAS exome AF: 0.0346

Gnomad FIN exome AF: 0.000962

Gnomad NFE exome AF: 0.00372

Gnomad OTH exome AF: 0.00536

GnomAD4 exome AF: 0.00522 AC: 7623 AN: 1459522 Hom.: 49 Cov.: 31 AF XY: 0.00509 AC XY: 3696 AN XY: 725920

African (AFR) AF: 0.00102 AC: 34 AN: 33470

American (AMR) AF: 0.00123 AC: 55 AN: 44632

Ashkenazi Jewish (ASJ) AF: 0.00613 AC: 160 AN: 26096

East Asian (EAS) AF: 0.0393 AC: 1561 AN: 39672

South Asian (SAS) AF: 0.00296 AC: 255 AN: 86018

European-Finnish (FIN) AF: 0.000749 AC: 39 AN: 52052

Middle Eastern (MID) AF: 0.00399 AC: 23 AN: 5766

European-Non Finnish (NFE) AF: 0.00457 AC: 5084 AN: 1111500

Other (OTH) AF: 0.00683 AC: 412 AN: 60316

GnomAD4 genome AF: 0.00396 AC: 602 AN: 152154 Hom.: 7 Cov.: 33 AF XY: 0.00397 AC XY: 295 AN XY: 74374

African (AFR) AF: 0.000964 AC: 40 AN: 41504

American (AMR) AF: 0.00261 AC: 40 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.00721 AC: 25 AN: 3468

East Asian (EAS) AF: 0.0408 AC: 211 AN: 5166

South Asian (SAS) AF: 0.00625 AC: 30 AN: 4800

European-Finnish (FIN) AF: 0.000283 AC: 3 AN: 10616

Middle Eastern (MID) AF: 0.00685 AC: 2 AN: 292

European-Non Finnish (NFE) AF: 0.00359 AC: 244 AN: 67990

Other (OTH) AF: 0.00237 AC: 5 AN: 2108

Alfa AF: 0.00293 Hom.: 1

Bravo AF: 0.00435

TwinsUK AF: 0.00378 AC: 14

ALSPAC AF: 0.00467 AC: 18

ESP6500AA AF: 0.000930 AC: 4

ESP6500EA AF: 0.00528 AC: 45

ExAC AF: 0.00490 AC: 591

Asia WGS AF: 0.0280 AC: 97 AN: 3478

EpiCase AF: 0.00403

EpiControl AF: 0.00351

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	10	not specified (12)
-	2	6	Peutz-Jeghers syndrome (8)
-	-	6	Hereditary cancer-predisposing syndrome (6)
-	-	6	not provided (6)
-	-	1	Breast and/or ovarian cancer (1)
-	-	1	Malignant tumor of breast (1)
-	-	1	Peutz-Jeghers syndrome;C0235974:Carcinoma of pancreas;C1336708:Germ cell tumor of testis;C1835047:Melanoma, cutaneous malignant, susceptibility to, 1 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.57
BayesDel_addAF	Benign	-0.56	T
BayesDel_noAF	Benign	-0.55
CADD	Benign	0.057
DANN	Benign	0.56
DEOGEN2	Benign	0.28	T
Eigen	Benign	-1.7
Eigen_PC	Benign	-1.9
FATHMM_MKL	Benign	0.0094	N
LIST_S2	Benign	0.74	T
MetaRNN	Benign	0.051	T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	1.8	L
PhyloP100		-1.1
PrimateAI	Uncertain	0.51	T
PROVEAN	Benign	-1.4	N
REVEL	Benign	0.16
Sift	Benign	0.24	T
Sift4G	Benign	0.57	T
Polyphen		0.062	B
Vest4		0.32
MutPred		0.79		Loss of stability (P = 0.0714)
MVP		0.38
MPC		0.046
ClinPred		0.0031	T
GERP RS		-7.5
PromoterAI		-0.055	Neutral
Varity_R		0.058
gMVP		0.19
Mutation Taster		=82/18	polymorphism

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

dbSNP: rs59912467; hg19: chr19-1223125; COSMIC: COSV58819912; COSMIC: COSV58819912;