19-1223175-G-A

Variant names:

• chr19-1223175-G-A
• rs755746417
• NM_000455.5:c.1108+3G>A

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_000455.5(STK11):​c.1108+3G>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000011 in 1,457,040 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: 0.000011 (0 hom.)
• Consequence: STK11 NM_000455.5 splice_region, intron
• Scores: Splicing: ADA: 0.0003884
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4 B:7
• Conservation: PhyloP100: 1.33
• 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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.58).
• BP6: Variant 19-1223175-G-A is Benign according to our data. Variant chr19-1223175-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 237787.
• BS1: Variant frequency is greater than expected in population mid. GnomAdExome4 allele frequency = 0.000011 (16/1457040) while in subpopulation MID AF = 0.000347 (2/5756). AF 95% confidence interval is 0.000061. There are 0 homozygotes in GnomAdExome4. There are 10 alleles in the male GnomAdExome4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High AC in GnomAdExome4 at 16 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.1108+3G>A		splice_region intron	N/A	NP_000446.1	A0A0S2Z4D1
	STK11	NM_001407255.1		c.1108+3G>A		splice_region intron	N/A	NP_001394184.1	Q15831-2
	STK11	NR_176325.1		n.2375+3G>A		splice_region intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	STK11	ENST00000326873.12	TSL:1 MANE Select	c.1108+3G>A		splice_region intron	N/A	ENSP00000324856.6	Q15831-1
	STK11	ENST00000652231.1		c.1108+3G>A		splice_region intron	N/A	ENSP00000498804.1	Q15831-2
	STK11	ENST00000585748.3	TSL:3	c.736+3G>A		splice_region intron	N/A	ENSP00000477641.2	A0A087WT72

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.0000209 AC: 5 AN: 239710 AF XY: 0.0000306

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.000102

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000277

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000110 AC: 16 AN: 1457040 Hom.: 0 Cov.: 31 AF XY: 0.0000138 AC XY: 10 AN XY: 724546

African (AFR) AF: 0.00 AC: 0 AN: 33448

American (AMR) AF: 0.0000225 AC: 1 AN: 44480

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26036

East Asian (EAS) AF: 0.00 AC: 0 AN: 39600

South Asian (SAS) AF: 0.0000117 AC: 1 AN: 85622

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51192

Middle Eastern (MID) AF: 0.000347 AC: 2 AN: 5756

European-Non Finnish (NFE) AF: 0.00000900 AC: 10 AN: 1110708

Other (OTH) AF: 0.0000332 AC: 2 AN: 60198

GnomAD4 genome Cov.: 33

Alfa AF: 0.000158 Hom.: 0

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	2	not specified (3)
-	-	3	Peutz-Jeghers syndrome (3)
-	1	1	Hereditary cancer-predisposing syndrome (2)
-	1	1	not provided (2)
-	1	-	Breast and/or ovarian cancer (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.58
CADD	Benign	16
DANN	Benign	0.85
PhyloP100		1.3
PromoterAI		0.010	Neutral

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00039
dbscSNV1_RF	Benign	0.018
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

Other links and lift over

dbSNP: rs755746417; hg19: chr19-1223174;