19-1222927-A-G

Variant names:

• chr19-1222927-A-G
• rs565029540
• NM_000455.5:c.921-58A>G

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_000455.5(STK11):​c.921-58A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000923 in 1,485,704 control chromosomes in the GnomAD database, including 13 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0044 (8 hom., cov: 33)
  • Exomes 𝑓: 0.00052 (5 hom.)
• Consequence: STK11 NM_000455.5 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.0270
• 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.94).
• BP6: Variant 19-1222927-A-G is Benign according to our data. Variant chr19-1222927-A-G is described in ClinVar as Benign. ClinVar VariationId is 560792.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00441 (671/152236) while in subpopulation AFR AF = 0.0154 (640/41520). AF 95% confidence interval is 0.0144. There are 8 homozygotes in GnomAd4. There are 305 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High AC in GnomAd4 at 671 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.921-58A>G		intron	N/A	NP_000446.1
	STK11	NM_001407255.1		c.921-58A>G		intron	N/A	NP_001394184.1
	STK11	NR_176325.1		n.2188-58A>G		intron	N/A

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	STK11	ENST00000326873.12	TSL:1 MANE Select	c.921-58A>G		intron	N/A	ENSP00000324856.6
	STK11	ENST00000652231.1		c.921-58A>G		intron	N/A	ENSP00000498804.1
	STK11	ENST00000585748.3	TSL:3	c.549-58A>G		intron	N/A	ENSP00000477641.2

Frequencies

GnomAD3 genomes AF: 0.00440 AC: 669 AN: 152118 Hom.: 8 Cov.: 33

Gnomad AFR AF: 0.0154

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00144

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00287

GnomAD4 exome AF: 0.000525 AC: 700 AN: 1333468 Hom.: 5 AF XY: 0.000397 AC XY: 258 AN XY: 650236

African (AFR) AF: 0.0178 AC: 536 AN: 30090

American (AMR) AF: 0.00111 AC: 34 AN: 30628

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 21386

East Asian (EAS) AF: 0.00 AC: 0 AN: 35178

South Asian (SAS) AF: 0.0000569 AC: 4 AN: 70348

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40720

Middle Eastern (MID) AF: 0.00224 AC: 10 AN: 4472

European-Non Finnish (NFE) AF: 0.0000450 AC: 47 AN: 1045472

Other (OTH) AF: 0.00125 AC: 69 AN: 55174

GnomAD4 genome AF: 0.00441 AC: 671 AN: 152236 Hom.: 8 Cov.: 33 AF XY: 0.00410 AC XY: 305 AN XY: 74438

African (AFR) AF: 0.0154 AC: 640 AN: 41520

American (AMR) AF: 0.00144 AC: 22 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68000

Other (OTH) AF: 0.00284 AC: 6 AN: 2114

Alfa AF: 0.00326 Hom.: 0

Bravo AF: 0.00504

Asia WGS AF: 0.000866 AC: 3 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Feb 10, 2017

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.94
CADD	Benign	1.1
DANN	Benign	0.34
PhyloP100		-0.027
PromoterAI		0.0026	Neutral
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs565029540; hg19: chr19-1222926;