Genetic Variant STK11:c.375-4C>T (chr19-1219320-C-T) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_000455.5(STK11):c.375-4C>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 2/2 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 34)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

STK11
NM_000455.5 splice_region, intron

Scores

Splicing: ADA: 0.00006808

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.239

Publications

0 publications found

Variant links:

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

STK11 links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.77).

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein
STK11	NM_000455.5 link	c.375-4C>T	splice_region_variant, intron_variant	Intron 2 of 9	ENST00000326873.12	NP_000446.1
STK11	NM_001407255.1 link	c.375-4C>T	splice_region_variant, intron_variant	Intron 2 of 8		NP_001394184.1
STK11	NR_176325.1 link	n.1642-4C>T	splice_region_variant, intron_variant	Intron 3 of 10

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	MANE	Protein
STK11	ENST00000326873.12 link	c.375-4C>T	splice_region_variant, intron_variant	Intron 2 of 9	1	NM_000455.5	ENSP00000324856.6
STK11	ENST00000652231.1 link	c.375-4C>T	splice_region_variant, intron_variant	Intron 2 of 8			ENSP00000498804.1
STK11	ENST00000585748.3 link	c.3-4C>T	splice_region_variant, intron_variant	Intron 4 of 11	3		ENSP00000477641.2
STK11	ENST00000593219.6 link	n.*200-4C>T	splice_region_variant, intron_variant	Intron 3 of 10	3		ENSP00000466610.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1428524

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

707572

African (AFR)

AF:

0.00

AC:

AN:

32798

American (AMR)

AF:

0.00

AC:

AN:

40042

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25512

East Asian (EAS)

AF:

0.00

AC:

AN:

37906

South Asian (SAS)

AF:

0.00

AC:

AN:

81272

European-Finnish (FIN)

AF:

0.00

AC:

AN:

50020

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5734

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1096026

Other (OTH)

AF:

0.00

AC:

AN:

59214

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.77

CADD

Benign

0.17

(source)

DANN

Benign

0.82

PhyloP100

-0.24

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.000068

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over