rs370976710

Variant names:

• chr19-1220601-G-A
• rs370976710
• NM_000455.5:c.618G>A

Your query was ambiguous. Multiple possible variants found:

• chr19-1220601-G-A
• chr19-1220601-G-C
• chr19-1220601-G-T

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 1P and 5B. PP3 BP6 BS2

The NM_000455.5(STK11):​c.618G>A​(p.Ala206Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000954 in 1,593,076 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. A206A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00016 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000088 (1 hom.)
• Consequence: STK11 NM_000455.5 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:14
• Conservation: PhyloP100: 2.24
• Publications: 5 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: Likely_benign. The variant received -4 ACMG points.

• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• BP6: Variant 19-1220601-G-A is Benign according to our data. Variant chr19-1220601-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 142319.
• BS2: High AC in GnomAd4 at 25 AD,Unknown 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.618G>A	p.Ala206Ala	synonymous	Exon 5 of 10	NP_000446.1	A0A0S2Z4D1
	STK11	NM_001407255.1		c.618G>A	p.Ala206Ala	synonymous	Exon 5 of 9	NP_001394184.1	Q15831-2
	STK11	NR_176325.1		n.1885G>A		non_coding_transcript_exon	Exon 6 of 11

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	STK11	ENST00000326873.12	TSL:1 MANE Select	c.618G>A	p.Ala206Ala	synonymous	Exon 5 of 10	ENSP00000324856.6	Q15831-1
	STK11	ENST00000652231.1		c.618G>A	p.Ala206Ala	synonymous	Exon 5 of 9	ENSP00000498804.1	Q15831-2
	STK11	ENST00000585748.3	TSL:3	c.246G>A	p.Ala82Ala	synonymous	Exon 7 of 12	ENSP00000477641.2	A0A087WT72

Frequencies

GnomAD3 genomes AF: 0.000164 AC: 25 AN: 152140 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00202

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00160

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.000479

GnomAD2 exomes AF: 0.000234 AC: 50 AN: 213928 AF XY: 0.000238

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00273

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00121

Gnomad NFE exome AF: 0.0000107

Gnomad OTH exome AF: 0.000185

GnomAD4 exome AF: 0.0000881 AC: 127 AN: 1440936 Hom.: 1 Cov.: 32 AF XY: 0.0000937 AC XY: 67 AN XY: 714970

African (AFR) AF: 0.00 AC: 0 AN: 33014

American (AMR) AF: 0.00 AC: 0 AN: 41984

Ashkenazi Jewish (ASJ) AF: 0.00222 AC: 57 AN: 25640

East Asian (EAS) AF: 0.00 AC: 0 AN: 38696

South Asian (SAS) AF: 0.0000119 AC: 1 AN: 84108

European-Finnish (FIN) AF: 0.000974 AC: 49 AN: 50332

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5650

European-Non Finnish (NFE) AF: 0.0000109 AC: 12 AN: 1102122

Other (OTH) AF: 0.000135 AC: 8 AN: 59390

GnomAD4 genome AF: 0.000164 AC: 25 AN: 152140 Hom.: 0 Cov.: 33 AF XY: 0.000296 AC XY: 22 AN XY: 74310

African (AFR) AF: 0.00 AC: 0 AN: 41422

American (AMR) AF: 0.00 AC: 0 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.00202 AC: 7 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5176

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00160 AC: 17 AN: 10626

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68014

Other (OTH) AF: 0.000479 AC: 1 AN: 2088

Alfa AF: 0.000261 Hom.: 0

Bravo AF: 0.0000642

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	5	Peutz-Jeghers syndrome (6)
-	1	3	Hereditary cancer-predisposing syndrome (4)
-	1	2	not specified (3)
-	-	2	not provided (2)
-	-	1	Breast and/or ovarian cancer (1)
-	-	1	Malignant tumor of breast (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.66
CADD	Benign	20
DANN	Benign	0.83
PhyloP100		2.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.58		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.58		Position offset: 2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs370976710; hg19: chr19-1220600;