5-172044949-C-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_005990.4(STK10):c.2840G>A(p.Cys947Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000533 in 1,614,192 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.00033 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00055 (1 hom.)
• Consequence: STK10 NM_005990.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.705

Genes affected

STK10 (HGNC:11388): (serine/threonine kinase 10) This gene encodes a member of the Ste20 family of serine/threonine protein kinases, and is similar to several known polo-like kinase kinases. The protein can associate with and phosphorylate polo-like kinase 1, and overexpression of a kinase-dead version of the protein interferes with normal cell cycle progression. The kinase can also negatively regulate interleukin 2 expression in T-cells via the mitogen activated protein kinase kinase 1 pathway. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.015869677).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
STK10	NM_005990.4	c.2840G>A	p.Cys947Tyr	missense_variant	19/19	ENST00000176763.10
STK10	XM_047417627.1	c.2450G>A	p.Cys817Tyr	missense_variant	16/16
STK10	XM_047417628.1	c.2291G>A	p.Cys764Tyr	missense_variant	18/18
STK10	XM_047417629.1	c.2156G>A	p.Cys719Tyr	missense_variant	17/17

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
STK10	ENST00000176763.10	c.2840G>A	p.Cys947Tyr	missense_variant	19/19	1	NM_005990.4	P1
STK10	ENST00000520476.1	c.714G>A	p.Val238=	synonymous_variant	7/7	2
STK10	ENST00000517360.1	n.346G>A		non_coding_transcript_exon_variant	2/2	2

Frequencies

GnomAD3 genomes AF: 0.000329 AC: 50 AN: 152182 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000262

Gnomad ASJ AF: 0.00115

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000942

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000544

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000469 AC: 118 AN: 251460 Hom.: 0 AF XY: 0.000500 AC XY: 68 AN XY: 135908

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000116

Gnomad ASJ exome AF: 0.00189

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.000231

Gnomad NFE exome AF: 0.000756

Gnomad OTH exome AF: 0.000489

GnomAD4 exome AF: 0.000554 AC: 810 AN: 1461890 Hom.: 1 Cov.: 31 AF XY: 0.000560 AC XY: 407 AN XY: 727246

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.000134

Gnomad4 ASJ exome AF: 0.00214

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000812

Gnomad4 FIN exome AF: 0.000300

Gnomad4 NFE exome AF: 0.000594

Gnomad4 OTH exome AF: 0.000778

GnomAD4 genome AF: 0.000328 AC: 50 AN: 152302 Hom.: 0 Cov.: 32 AF XY: 0.000295 AC XY: 22 AN XY: 74476

Gnomad4 AFR AF: 0.0000722

Gnomad4 AMR AF: 0.000261

Gnomad4 ASJ AF: 0.00115

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0000942

Gnomad4 NFE AF: 0.000544

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.000806 Hom.: 0

Bravo AF: 0.000351

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000581 AC: 5

ExAC AF: 0.000544 AC: 66

EpiCase AF: 0.00104

EpiControl AF: 0.000948

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 26, 2021

The c.2840G>A (p.C947Y) alteration is located in exon 19 (coding exon 19) of the STK10 gene. This alteration results from a G to A substitution at nucleotide position 2840, causing the cysteine (C) at amino acid position 947 to be replaced by a tyrosine (Y). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.071
BayesDel_addAF	Benign	-0.43	T
BayesDel_noAF	Benign	-0.48
Cadd	Benign	16
Dann	Benign	0.87
DEOGEN2	Uncertain	0.48	T
Eigen	Benign	-0.64
Eigen_PC	Benign	-0.63
FATHMM_MKL	Benign	0.11	N
LIST_S2	Uncertain	0.86	D
M_CAP	Benign	0.010	T
MetaRNN	Benign	0.016	T
MetaSVM	Benign	-0.89	T
MutationAssessor	Benign	1.1	L
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.40	T
PROVEAN	Uncertain	-4.1	D
REVEL	Benign	0.13
Sift	Benign	0.065	T
Sift4G	Benign	0.82	T
Polyphen		0.0020	B
Vest4		0.13
MVP		0.59
MPC		0.53
ClinPred		0.054	T
GERP RS		4.1
Varity_R		0.31
gMVP		0.19

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

Publications

LitVar

Other links and lift over

dbSNP: rs56355550; hg19: chr5-171471953; COSMIC: COSV99075190;