19-1219411-C-T

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_Moderate BP6 BP7 BS1

The NM_000455.5(STK11):c.462C>T(p.His154=) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000186 in 912,308 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.000019 (0 hom.)
• Consequence: STK11 NM_000455.5 splice_region, synonymous
• Scores: Splicing: ADA: 0.06533
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:3
• Conservation: PhyloP100: -0.219

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 -8 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.42).
• BP6: Variant 19-1219411-C-T is Benign according to our data. Variant chr19-1219411-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 184352.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Uncertain_significance=1}.
• BP7: Synonymous conserved (PhyloP=-0.219 with no splicing effect.
• BS1: Variant frequency is greater than expected in population eas. gnomad4_exome allele frequency = 0.0000186 (17/912308) while in subpopulation EAS AF= 0.000548 (8/14594). AF 95% confidence interval is 0.000272. There are 0 homozygotes in gnomad4_exome. There are 10 alleles in male gnomad4_exome subpopulation. Median coverage is 38. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
STK11	NM_000455.5	c.462C>T	p.His154=	splice_region_variant, synonymous_variant	3/10	ENST00000326873.12
STK11	NM_001407255.1	c.462C>T	p.His154=	splice_region_variant, synonymous_variant	3/9
STK11	NR_176325.1	n.1729C>T		splice_region_variant, non_coding_transcript_exon_variant	4/11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
STK11	ENST00000326873.12	c.462C>T	p.His154=	splice_region_variant, synonymous_variant	3/10	1	NM_000455.5	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.0000102 AC: 2 AN: 195934 Hom.: 0 AF XY: 0.00000946 AC XY: 1 AN XY: 105692

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000345

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000701

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: 0.0000186 AC: 17 AN: 912308 Hom.: 0 Cov.: 38 AF XY: 0.0000217 AC XY: 10 AN XY: 461604

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000297

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000548

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000117

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Hereditary cancer-predisposing syndrome Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Jun 20, 2018	- -
Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Oct 14, 2014	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. -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Aug 15, 2023

- -

Malignant tumor of breast Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

-

The STK11 p.His154= variant was not identified in the literature nor was it identified in the LOVD 3.0, database. The variant was identified in dbSNP (ID: rs786201418) as "With Likely benign allele", ClinVar (classified as likely benign by Ambry Genetics and Invitae).The variant was identified in control databases in 2 of 191394 chromosomes at a frequency of 0.00001 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: Latino in 1 of 28254 chromosomes (freq: 0.000035), East Asian in 1 of 13542 chromosomes (freq: 0.00007), while the variant was not observed in the African, Other, European Non-Finnish, Ashkenazi Jewish, European Finnish, and South Asian populations. The p.His154= variant is not expected to have clinical significance because it does not result in a change of amino acid. The variant occurs outside of the splicing consensus sequence and 1 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) 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. This variant is classified as a variant of uncertain significance. -

Peutz-Jeghers syndrome Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Nov 23, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.42
Cadd	Benign	0.37
Dann	Benign	0.80
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.065
dbscSNV1_RF	Benign	0.31
SpliceAI score (max)		0.030		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: rs786201418; hg19: chr19-1219410; COSMIC: COSV58829277; COSMIC: COSV58829277;