rs376313955

Variant names:

• chr19-1219422-G-A
• rs376313955
• NM_000455.5:c.464+9G>A

Your query was ambiguous. Multiple possible variants found:

• chr19-1219422-G-A
• chr19-1219422-G-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+9G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000354 in 1,554,658 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0020 (3 hom., cov: 34)
  • Exomes 𝑓: 0.00018 (0 hom.)
• Consequence: STK11 NM_000455.5 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:18
• Conservation: PhyloP100: -1.57
• Publications: 2 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.79).
• BP6: Variant 19-1219422-G-A is Benign according to our data. Variant chr19-1219422-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 139331.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00195 (291/149216) while in subpopulation AFR AF = 0.00663 (268/40450). AF 95% confidence interval is 0.00597. There are 3 homozygotes in GnomAd4. There are 141 alleles in the male GnomAd4 subpopulation. Median coverage is 34. This position passed quality control check.
• BS2: High AC in GnomAd4 at 291 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.464+9G>A		intron	N/A	NP_000446.1	A0A0S2Z4D1
	STK11	NM_001407255.1		c.464+9G>A		intron	N/A	NP_001394184.1	Q15831-2
	STK11	NR_176325.1		n.1731+9G>A		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	STK11	ENST00000326873.12	TSL:1 MANE Select	c.464+9G>A		intron	N/A	ENSP00000324856.6	Q15831-1
	STK11	ENST00000652231.1		c.464+9G>A		intron	N/A	ENSP00000498804.1	Q15831-2
	STK11	ENST00000585748.3	TSL:3	c.92+9G>A		intron	N/A	ENSP00000477641.2	A0A087WT72

Frequencies

GnomAD3 genomes AF: 0.00195 AC: 291 AN: 149100 Hom.: 3 Cov.: 34

Gnomad AFR AF: 0.00665

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00100

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00321

Gnomad NFE AF: 0.0000445

Gnomad OTH AF: 0.00196

GnomAD2 exomes AF: 0.000578 AC: 103 AN: 178206 AF XY: 0.000428

Gnomad AFR exome AF: 0.00721

Gnomad AMR exome AF: 0.00107

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000779

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000133

Gnomad OTH exome AF: 0.000209

GnomAD4 exome AF: 0.000185 AC: 260 AN: 1405442 Hom.: 0 Cov.: 49 AF XY: 0.000173 AC XY: 120 AN XY: 695236

African (AFR) AF: 0.00598 AC: 193 AN: 32256

American (AMR) AF: 0.000834 AC: 32 AN: 38390

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24940

East Asian (EAS) AF: 0.0000292 AC: 1 AN: 34224

South Asian (SAS) AF: 0.00 AC: 0 AN: 80720

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 48096

Middle Eastern (MID) AF: 0.000551 AC: 3 AN: 5442

European-Non Finnish (NFE) AF: 0.0000111 AC: 12 AN: 1083536

Other (OTH) AF: 0.000329 AC: 19 AN: 57838

GnomAD4 genome AF: 0.00195 AC: 291 AN: 149216 Hom.: 3 Cov.: 34 AF XY: 0.00194 AC XY: 141 AN XY: 72752

African (AFR) AF: 0.00663 AC: 268 AN: 40450

American (AMR) AF: 0.00100 AC: 15 AN: 14962

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3426

East Asian (EAS) AF: 0.00 AC: 0 AN: 4738

South Asian (SAS) AF: 0.00 AC: 0 AN: 4648

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10312

Middle Eastern (MID) AF: 0.00350 AC: 1 AN: 286

European-Non Finnish (NFE) AF: 0.0000445 AC: 3 AN: 67436

Other (OTH) AF: 0.00195 AC: 4 AN: 2052

Alfa AF: 0.00163 Hom.: 0

Bravo AF: 0.00218

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	Peutz-Jeghers syndrome (5)
-	-	4	Hereditary cancer-predisposing syndrome (4)
-	-	3	not provided (3)
-	-	3	not specified (3)
-	-	1	Breast and/or ovarian cancer (1)
-	-	1	Malignant tumor of breast (1)
-	-	1	STK11-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	0.55
DANN	Benign	0.95
PhyloP100		-1.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
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: rs376313955; hg19: chr19-1219421;