19-1226629-G-C

Variant names:

• chr19-1226629-G-C
• rs369097329
• NM_000455.5:c.1284G>C

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_000455.5(STK11):​c.1284G>C​(p.Ser428Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000973 in 1,542,340 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 Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. S428S) has been classified as Benign.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000010 (0 hom.)
• Consequence: STK11 NM_000455.5 synonymous
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -1.85

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]

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.53).
• BP6: Variant 19-1226629-G-C is Benign according to our data. Variant chr19-1226629-G-C is described in ClinVar as [Likely_benign]. Clinvar id is 184606.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-1226629-G-C is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-1.85 with no splicing effect.
• BS1: Variant frequency is greater than expected in population eas. gnomad4_exome allele frequency = 0.0000101 (14/1390104) while in subpopulation EAS AF= 0.000196 (7/35652). AF 95% confidence interval is 0.0000912. There are 0 homozygotes in gnomad4_exome. There are 7 alleles in male gnomad4_exome subpopulation. Median coverage is 31. This position pass quality control queck.
• BS2: High AC in GnomAdExome4 at 14 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
STK11	NM_000455.5	c.1284G>C	p.Ser428Ser	synonymous_variant	Exon 9 of 10	ENST00000326873.12	NP_000446.1
STK11	NR_176325.1	n.2551G>C		non_coding_transcript_exon_variant	Exon 10 of 11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
STK11	ENST00000326873.12	c.1284G>C	p.Ser428Ser	synonymous_variant	Exon 9 of 10	1	NM_000455.5	ENSP00000324856.6
STK11	ENST00000585748.3	c.912G>C	p.Ser304Ser	synonymous_variant	Exon 11 of 12	3		ENSP00000477641.2

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152236 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000356 AC: 5 AN: 140466 Hom.: 0 AF XY: 0.0000260 AC XY: 2 AN XY: 76974

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000474

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000101 AC: 14 AN: 1390104 Hom.: 0 Cov.: 31 AF XY: 0.0000102 AC XY: 7 AN XY: 685362

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000196

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.29e-7

Gnomad4 OTH exome AF: 0.000104

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152236 Hom.: 0 Cov.: 33 AF XY: 0.0000134 AC XY: 1 AN XY: 74376

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Asia WGS AF: 0.000866 AC: 3 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Peutz-Jeghers syndrome Benign:2

Jan 14, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 06, 2023

All of Us Research Program, National Institutes of Health

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hereditary cancer-predisposing syndrome Benign:2

Apr 28, 2016

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Sep 02, 2016

Color Diagnostics, LLC DBA Color Health

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Malignant neoplasm of brain Benign:1

-

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

The STK11 p.Ser428= variant was not identified in the literature. The variant was identified in dbSNP (ID: rs369097329) as “With Likely benign allele”, ClinVar (3x as likely benign by Ambry Genetics, Invitae, Color) and LOVD 3.0 (1x as benign). The variant was identified in control databases in 5 of 135876 chromosomes at a frequency of 0.000037 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: East Asian in 5 of 9960 chromosomes (freq: 0.0005), but not in the African, Other, Latino, European Non-Finnish, Ashkenazi Jewish, European Finnish or South Asian populations. The p.Ser428= variant is not expected to have clinical significance because it does not result in a change of amino acid and is not located in a known consensus splice site. In addition, in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign. -

Malignant tumor of breast Benign:1

-

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

The STK11 p.Ser428= variant was not identified in the literature. The variant was identified in dbSNP (ID: rs369097329) as “With Likely benign allele”, ClinVar (3x as likely benign by Ambry Genetics, Invitae, Color) and LOVD 3.0 (1x as benign). The variant was identified in control databases in 5 of 135876 chromosomes at a frequency of 0.000037 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: East Asian in 5 of 9960 chromosomes (freq: 0.0005), but not in the African, Other, Latino, European Non-Finnish, Ashkenazi Jewish, European Finnish or South Asian populations. The p.Ser428= variant is not expected to have clinical significance because it does not result in a change of amino acid and is not located in a known consensus splice site. In addition, in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.53
CADD	Benign	0.021
DANN	Benign	0.80
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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

LitVar

Other links and lift over

dbSNP: rs369097329; hg19: chr19-1226628;