rs786201418

Variant names:

• chr19-1219411-C-T
• rs786201418
• NM_000455.5:c.462C>T

Your query was ambiguous. Multiple possible variants found:

• chr19-1219411-C-T
• chr19-1219411-C-A
• chr19-1219411-C-G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Moderate BP6 BP7 BS1 BS2

The NM_000455.5(STK11):​c.462C>T​(p.His154His) 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:4
• Conservation: PhyloP100: -0.219
• Publications: 1 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: ClinGen, Labcorp Genetics (formerly Invitae), G2P, Genomics England PanelApp, Orphanet
• familial ovarian cancer

  Inheritance: Unknown Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -12 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 VariationId is 184352.
• BP7: Synonymous conserved (PhyloP=-0.219 with no splicing effect.
• BS1: Variant frequency is greater than expected in population eas. GnomAdExome4 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 GnomAdExome4. There are 10 alleles in the male GnomAdExome4 subpopulation. Median coverage is 38. This position passed quality control check.
• BS2: High AC in GnomAdExome4 at 17 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	STK11	NM_000455.5	MANE Select	c.462C>T	p.His154His	splice_region synonymous	Exon 3 of 10	NP_000446.1	A0A0S2Z4D1
	STK11	NM_001407255.1		c.462C>T	p.His154His	splice_region synonymous	Exon 3 of 9	NP_001394184.1	Q15831-2
	STK11	NR_176325.1		n.1729C>T		splice_region non_coding_transcript_exon	Exon 4 of 11

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	STK11	ENST00000326873.12	TSL:1 MANE Select	c.462C>T	p.His154His	splice_region synonymous	Exon 3 of 10	ENSP00000324856.6	Q15831-1
	STK11	ENST00000652231.1		c.462C>T	p.His154His	splice_region synonymous	Exon 3 of 9	ENSP00000498804.1	Q15831-2
	STK11	ENST00000585748.3	TSL:3	c.90C>T	p.His30His	splice_region synonymous	Exon 5 of 12	ENSP00000477641.2	A0A087WT72

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.0000102 AC: 2 AN: 195934 AF XY: 0.00000946

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 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

African (AFR) AF: 0.00 AC: 0 AN: 20726

American (AMR) AF: 0.0000297 AC: 1 AN: 33696

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 15708

East Asian (EAS) AF: 0.000548 AC: 8 AN: 14594

South Asian (SAS) AF: 0.00 AC: 0 AN: 72838

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 30910

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3900

European-Non Finnish (NFE) AF: 0.0000117 AC: 8 AN: 685276

Other (OTH) AF: 0.00 AC: 0 AN: 34660

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	2	Hereditary cancer-predisposing syndrome (2)
-	-	2	Peutz-Jeghers syndrome (2)
-	1	-	Malignant tumor of breast (1)
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.42
CADD	Benign	0.37
DANN	Benign	0.80
PhyloP100		-0.22
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

Other links and lift over

dbSNP: rs786201418; hg19: chr19-1219410; COSMIC: COSV58829277;