NM_000455.5:c.464+12G>C

Variant names:

• chr19-1219425-G-C
• rs113069959
• NM_000455.5:c.464+12G>C

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.464+12G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000564 in 1,418,104 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: not found (cov: 34)
  • Exomes 𝑓: 0.0000056 (0 hom.)
• Consequence: STK11 NM_000455.5 intron
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.11
• Publications: 0 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: Labcorp Genetics (formerly Invitae), ClinGen, Orphanet, Genomics England PanelApp, G2P
• familial ovarian cancer

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BP6: Variant 19-1219425-G-C is Benign according to our data. Variant chr19-1219425-G-C is described in ClinVar as Likely_benign. ClinVar VariationId is 492528.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAdExome4 allele frequency = 0.00000564 (8/1418104) while in subpopulation AFR AF = 0.000153 (5/32622). AF 95% confidence interval is 0.0000597. There are 0 homozygotes in GnomAdExome4. There are 5 alleles in the male GnomAdExome4 subpopulation. Median coverage is 49. This position passed quality control check.
• BS2: High AC in GnomAdExome4 at 8 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	STK11	NM_000455.5	MANE Select	c.464+12G>C		intron	N/A	NP_000446.1
	STK11	NM_001407255.1		c.464+12G>C		intron	N/A	NP_001394184.1
	STK11	NR_176325.1		n.1731+12G>C		intron	N/A

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	STK11	ENST00000326873.12	TSL:1 MANE Select	c.464+12G>C		intron	N/A	ENSP00000324856.6
	STK11	ENST00000652231.1		c.464+12G>C		intron	N/A	ENSP00000498804.1
	STK11	ENST00000585748.3	TSL:3	c.92+12G>C		intron	N/A	ENSP00000477641.2

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome AF: 0.00000564 AC: 8 AN: 1418104 Hom.: 0 Cov.: 49 AF XY: 0.00000713 AC XY: 5 AN XY: 701418

African (AFR) AF: 0.000153 AC: 5 AN: 32622

American (AMR) AF: 0.00 AC: 0 AN: 38534

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25370

East Asian (EAS) AF: 0.00 AC: 0 AN: 37346

South Asian (SAS) AF: 0.00 AC: 0 AN: 80702

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 48804

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5528

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1090470

Other (OTH) AF: 0.0000511 AC: 3 AN: 58728

GnomAD4 genome Cov.: 34

Asia WGS AF: 0.000866 AC: 3 AN: 3476

ClinVar

ClinVar submissions as Germline

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Hereditary cancer-predisposing syndrome (1)
-	-	1	Peutz-Jeghers syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	1.3
DANN	Benign	0.46
PhyloP100		1.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs113069959; hg19: chr19-1219424;