19-1220519-A-AG

Variant names:

• chr19-1220519-A-AG
• rs534445875
• NM_000455.5:c.597+21dupG

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_Strong BS1 BS2

The NM_000455.5(STK11):​c.597+21dupG variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000382 in 1,593,380 control chromosomes in the GnomAD database, including 2 homozygotes. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00054 (1 hom., cov: 33)
  • Exomes 𝑓: 0.00037 (1 hom.)
• Consequence: STK11 NM_000455.5 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: -1.36
• 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: 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 -16 ACMG points.

• BP6: Variant 19-1220519-A-AG is Benign according to our data. Variant chr19-1220519-A-AG is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 328230.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.00054 (82/151900) while in subpopulation AMR AF = 0.00177 (27/15224). AF 95% confidence interval is 0.00125. There are 1 homozygotes in GnomAd4. There are 43 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High AC in GnomAd4 at 82 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.597+21dupG		intron	N/A	NP_000446.1
	STK11	NM_001407255.1		c.597+21dupG		intron	N/A	NP_001394184.1
	STK11	NR_176325.1		n.1864+21dupG		intron	N/A

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	STK11	ENST00000326873.12	TSL:1 MANE Select	c.597+21dupG		intron	N/A	ENSP00000324856.6
	STK11	ENST00000652231.1		c.597+21dupG		intron	N/A	ENSP00000498804.1
	STK11	ENST00000585748.3	TSL:3	c.225+21dupG		intron	N/A	ENSP00000477641.2

Frequencies

GnomAD3 genomes AF: 0.000534 AC: 81 AN: 151782 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.000678

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00178

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00135

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000206

Gnomad OTH AF: 0.00144

GnomAD2 exomes AF: 0.000408 AC: 88 AN: 215782 AF XY: 0.000408

Gnomad AFR exome AF: 0.000161

Gnomad AMR exome AF: 0.000857

Gnomad ASJ exome AF: 0.000109

Gnomad EAS exome AF: 0.00119

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000284

Gnomad OTH exome AF: 0.000371

GnomAD4 exome AF: 0.000366 AC: 527 AN: 1441480 Hom.: 1 Cov.: 32 AF XY: 0.000352 AC XY: 252 AN XY: 715240

African (AFR) AF: 0.000362 AC: 12 AN: 33142

American (AMR) AF: 0.000963 AC: 41 AN: 42590

Ashkenazi Jewish (ASJ) AF: 0.0000391 AC: 1 AN: 25588

East Asian (EAS) AF: 0.00131 AC: 51 AN: 38956

South Asian (SAS) AF: 0.000309 AC: 26 AN: 84066

European-Finnish (FIN) AF: 0.0000394 AC: 2 AN: 50700

Middle Eastern (MID) AF: 0.000350 AC: 2 AN: 5714

European-Non Finnish (NFE) AF: 0.000337 AC: 371 AN: 1101248

Other (OTH) AF: 0.000353 AC: 21 AN: 59476

GnomAD4 genome AF: 0.000540 AC: 82 AN: 151900 Hom.: 1 Cov.: 33 AF XY: 0.000579 AC XY: 43 AN XY: 74282

African (AFR) AF: 0.000700 AC: 29 AN: 41438

American (AMR) AF: 0.00177 AC: 27 AN: 15224

Ashkenazi Jewish (ASJ) AF: 0.000288 AC: 1 AN: 3468

East Asian (EAS) AF: 0.00136 AC: 7 AN: 5162

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10594

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000206 AC: 14 AN: 67872

Other (OTH) AF: 0.00142 AC: 3 AN: 2112

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.000722

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	Peutz-Jeghers syndrome (5)
-	-	2	not provided (2)
-	-	2	not specified (2)
-	-	1	Breast and/or ovarian cancer (1)
-	-	1	Hereditary cancer-predisposing syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-1.4
Mutation Taster		=100/0	polymorphism

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

Other links and lift over

dbSNP: rs534445875; hg19: chr19-1220518;