19-1221935-C-T

Variant names:

• chr19-1221935-C-T
• rs756001994
• NM_000455.5:c.863-14C>T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_000455.5(STK11):​c.863-14C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000329 in 1,551,914 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 (★★).

• Frequency:
  • Genomes: 𝑓 0.000079 (0 hom., cov: 34)
  • Exomes 𝑓: 0.000028 (0 hom.)
• Consequence: STK11 NM_000455.5 intron
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -2.82

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 19-1221935-C-T is Benign according to our data. Variant chr19-1221935-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 378678.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0000788 (12/152242) while in subpopulation AFR AF= 0.000193 (8/41466). AF 95% confidence interval is 0.0000956. There are 0 homozygotes in gnomad4. There are 6 alleles in male gnomad4 subpopulation. Median coverage is 34. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 12 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
STK11	NM_000455.5	c.863-14C>T		intron_variant	Intron 6 of 9	ENST00000326873.12	NP_000446.1
STK11	NM_001407255.1	c.863-14C>T		intron_variant	Intron 6 of 8		NP_001394184.1
STK11	NR_176325.1	n.2130-14C>T		intron_variant	Intron 7 of 10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
STK11	ENST00000326873.12	c.863-14C>T		intron_variant	Intron 6 of 9	1	NM_000455.5	ENSP00000324856.6
STK11	ENST00000652231.1	c.863-14C>T		intron_variant	Intron 6 of 8			ENSP00000498804.1
STK11	ENST00000585748.3	c.491-14C>T		intron_variant	Intron 8 of 11	3		ENSP00000477641.2

Frequencies

GnomAD3 genomes AF: 0.0000788 AC: 12 AN: 152242 Hom.: 0 Cov.: 34

Gnomad AFR AF: 0.000193

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: 0.0000941

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000576 AC: 9 AN: 156172 Hom.: 0 AF XY: 0.0000722 AC XY: 6 AN XY: 83108

Gnomad AFR exome AF: 0.000124

Gnomad AMR exome AF: 0.000120

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000898

Gnomad SAS exome AF: 0.0000437

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000328

Gnomad OTH exome AF: 0.000228

GnomAD4 exome AF: 0.0000279 AC: 39 AN: 1399672 Hom.: 0 Cov.: 30 AF XY: 0.0000391 AC XY: 27 AN XY: 690640

Gnomad4 AFR exome AF: 0.0000632

Gnomad4 AMR exome AF: 0.0000834

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000279

Gnomad4 SAS exome AF: 0.0000504

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000213

Gnomad4 OTH exome AF: 0.000103

GnomAD4 genome AF: 0.0000788 AC: 12 AN: 152242 Hom.: 0 Cov.: 34 AF XY: 0.0000807 AC XY: 6 AN XY: 74376

Gnomad4 AFR AF: 0.000193

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0000941

Gnomad4 NFE AF: 0.0000441

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.0000567

ClinVar

Significance: Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Peutz-Jeghers syndrome Benign:3

Dec 01, 2023

All of Us Research Program, National Institutes of Health

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 07, 2023

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dec 23, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Benign:2

Mar 04, 2025

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 17, 2015

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

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 c.863-14C>T variant was not identified in the literature, nor was it identified in the Cosmic, LOVD 3.0, Zhejiang University Database, or Insight Hereditary Tumors databases. The variant was identified in dbSNP (ID: rs756001994 as "With Likely benign, Uncertain significance allele") and in ClinVar (2x as likely benign by GeneDx and Color Genomics). The variant was identified in control databases in 12 of 181762 chromosomes at a frequency of 0.00007 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: African in 4 of 16456 chromosomes (freq: 0.0002), Other in 1 of 4832 chromosomes (freq: 0.0002), Latino in 3 of 25082 chromosomes (freq: 0.0001), European in 2 of 73216 chromosomes (freq: 0.00003), East Asian in 1 of 12088 chromosomes (freq: 0.00008), and South Asian in 1 of 22908 chromosomes (freq: 0.00004), while the variant was not observed in the Ashkenazi Jewish or Finnish populations. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) 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. -

Hereditary cancer-predisposing syndrome Benign:1

Apr 18, 2016

Color Diagnostics, LLC DBA Color Health

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	0.076
DANN	Benign	0.55
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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: rs756001994; hg19: chr19-1221934;