rs786201244

Variant names:

• chr19-1226611-C-T
• rs751352435
• NM_000455.5:c.1266C>T

Your query was ambiguous. Multiple possible variants found:

• chr19-1226611-C-T
• chr19-1226611-C-G
• chr19-1226611-C-A

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP6

The NM_000455.5(STK11):​c.1266C>T​(p.Ser422Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000214 in 1,404,256 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 Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: STK11 NM_000455.5 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:1
• Conservation: PhyloP100: 3.11

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 Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP6: Variant 19-1226611-C-T is Benign according to our data. Variant chr19-1226611-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 184045.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=2}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
STK11	NM_000455.5	c.1266C>T	p.Ser422Ser	synonymous_variant	Exon 9 of 10	ENST00000326873.12	NP_000446.1
STK11	NR_176325.1	n.2533C>T		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.1266C>T	p.Ser422Ser	synonymous_variant	Exon 9 of 10	1	NM_000455.5	ENSP00000324856.6
STK11	ENST00000585748.3	c.894C>T	p.Ser298Ser	synonymous_variant	Exon 11 of 12	3		ENSP00000477641.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000214 AC: 3 AN: 1404256 Hom.: 0 Cov.: 31 AF XY: 0.00000144 AC XY: 1 AN XY: 693598

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000273

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0000419

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Peutz-Jeghers syndrome Uncertain:2

Aug 18, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. ClinVar contains an entry for this variant (Variation ID: 184045). This variant has not been reported in the literature in individuals affected with STK11-related conditions. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This sequence change affects codon 422 of the STK11 mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the STK11 protein. -

Jul 15, 2021

Genome-Nilou Lab

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hereditary cancer-predisposing syndrome Benign:1

Jul 08, 2014

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: 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.37
CADD	Benign	20
DANN	Benign	0.96
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.48		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.48		Position offset: -2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs751352435; hg19: chr19-1226610;