Genetic Variant SBK1:p.Pro275Thr (chr16-28320469-C-A) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_001024401.3(SBK1):c.823C>A(p.Pro275Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000211 in 1,422,412 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 31)

Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

SBK1
NM_001024401.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.603

Variant links:

Genes affected

SBK1 (HGNC:17699): (SH3 domain binding kinase 1) Predicted to enable protein serine/threonine kinase activity. Predicted to be involved in peptidyl-serine phosphorylation and peptidyl-threonine phosphorylation. Predicted to be located in cytoplasm. [provided by Alliance of Genome Resources, Apr 2022]

SBK1 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.25198013).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SBK1	NM_001024401.3 link	c.823C>A	p.Pro275Thr	missense_variant	Exon 4 of 4	ENST00000341901.5	NP_001019572.1	Q52WX2
SBK1	XM_005255315.5 link	c.925C>A	p.Pro309Thr	missense_variant	Exon 4 of 4		XP_005255372.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SBK1	ENST00000341901.5 link	c.823C>A	p.Pro275Thr	missense_variant	Exon 4 of 4	1	NM_001024401.3	ENSP00000343248.4		Q52WX2
SBK1	ENST00000671413.3 link	c.1087C>A	p.Pro363Thr	missense_variant	Exon 4 of 4			ENSP00000499661.3		A0A590UK17

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000485

AC:

AN:

206186

Hom.:

AF XY:

0.00000862

AC XY:

AN XY:

116022

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000107

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000211

AC:

AN:

1422412

Hom.:

Cov.:

AF XY:

0.00000283

AC XY:

AN XY:

707806

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000273

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

May 23, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.823C>A (p.P275T) alteration is located in exon 4 (coding exon 3) of the SBK1 gene. This alteration results from a C to A substitution at nucleotide position 823, causing the proline (P) at amino acid position 275 to be replaced by a threonine (T). 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

0.12

BayesDel_addAF

Benign

-0.16

BayesDel_noAF

Benign

-0.46

CADD

Benign

DANN

Uncertain

0.98

DEOGEN2

Benign

0.026

Eigen

Benign

-0.41

Eigen_PC

Benign

-0.32

FATHMM_MKL

Benign

0.63

LIST_S2

Benign

0.84

M_CAP

Pathogenic

0.80

MetaRNN

Benign

0.25

MetaSVM

Benign

-0.85

MutationAssessor

Benign

1.2

PrimateAI

Uncertain

0.79

PROVEAN

Benign

-0.59

REVEL

Benign

0.040

Sift

Benign

0.083

Sift4G

Benign

0.12

Polyphen

0.029

Vest4

0.093

MutPred

0.42

Gain of phosphorylation at P275 (P = 0.0438);

MVP

0.65

ClinPred

0.10

GERP RS

1.7

Varity_R

0.13

gMVP

0.81

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over