19-1206815-C-T

Variant names:

• chr19-1206815-C-T
• rs1407068597
• NM_000455.5:c.-99C>T

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Strong BP6_Moderate

The NM_000455.5(STK11):​c.-99C>T variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. There is a variant allele frequency bias in the population database for this variant (GnomAdExome4), which may indicate mosaicism or somatic mutations in the reference population data. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.00011 (0 hom., cov: 31)
  • Exomes 𝑓: 0.0022 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: STK11 NM_000455.5 5_prime_UTR
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -2.02
• 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: Likely_benign. The variant received -6 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.71).
• BP6: Variant 19-1206815-C-T is Benign according to our data. Variant chr19-1206815-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 803513.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
STK11	NM_000455.5	c.-99C>T		5_prime_UTR_variant	Exon 1 of 10	ENST00000326873.12	NP_000446.1
STK11	NR_176325.1	n.1038C>T		non_coding_transcript_exon_variant	Exon 1 of 11
STK11	NM_001407255.1	c.-99C>T		5_prime_UTR_variant	Exon 1 of 9		NP_001394184.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
STK11	ENST00000326873.12	c.-99C>T		5_prime_UTR_variant	Exon 1 of 10	1	NM_000455.5	ENSP00000324856.6
STK11	ENST00000652231.1	c.-99C>T		5_prime_UTR_variant	Exon 1 of 9			ENSP00000498804.1
STK11	ENST00000585748.3	c.-82-11602C>T		intron_variant	Intron 3 of 11	3		ENSP00000477641.2
STK11	ENST00000593219.6	n.-99C>T		upstream_gene_variant		3		ENSP00000466610.1

Frequencies

GnomAD3 genomes AF: 0.000108 AC: 16 AN: 148028 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.0000499

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000671

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000729

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000896

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00221 AC: 2555 AN: 1154754 Hom.: 0 Cov.: 20 AF XY: 0.00246 AC XY: 1375 AN XY: 558582

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00325 AC: 82 AN: 25238

American (AMR) AF: 0.00941 AC: 152 AN: 16152

Ashkenazi Jewish (ASJ) AF: 0.00390 AC: 67 AN: 17190

East Asian (EAS) AF: 0.00500 AC: 156 AN: 31190

South Asian (SAS) AF: 0.0101 AC: 472 AN: 46584

European-Finnish (FIN) AF: 0.00446 AC: 150 AN: 33666

Middle Eastern (MID) AF: 0.00397 AC: 14 AN: 3528

European-Non Finnish (NFE) AF: 0.00144 AC: 1345 AN: 933270

Other (OTH) AF: 0.00244 AC: 117 AN: 47936

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.000108 AC: 16 AN: 148028 Hom.: 0 Cov.: 31 AF XY: 0.000153 AC XY: 11 AN XY: 71990

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0000499 AC: 2 AN: 40052

American (AMR) AF: 0.0000671 AC: 1 AN: 14912

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3436

East Asian (EAS) AF: 0.00 AC: 0 AN: 5116

South Asian (SAS) AF: 0.00 AC: 0 AN: 4700

European-Finnish (FIN) AF: 0.000729 AC: 7 AN: 9598

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

European-Non Finnish (NFE) AF: 0.0000896 AC: 6 AN: 66974

Other (OTH) AF: 0.00 AC: 0 AN: 2032

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00205 Hom.: 0

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Peutz-Jeghers syndrome Benign:1

May 28, 2019

Mendelics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.71
CADD	Benign	1.2
DANN	Benign	0.93
PhyloP100		-2.0
PromoterAI		0.013	Neutral

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: rs1407068597; hg19: chr19-1206814;