Genetic Variant SBK2:p.Arg305Gln (chr19-55529866-C-T) – 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_001370096.2(SBK2):c.914G>A(p.Arg305Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000382 in 1,598,354 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000033 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000039 ( 0 hom. )

Consequence

SBK2
NM_001370096.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.00200

Variant links:

Genes affected

SBK2 (HGNC:34416): (SH3 domain binding kinase family member 2) Predicted to enable MAP kinase kinase activity. Predicted to be involved in MAPK cascade and protein phosphorylation. [provided by Alliance of Genome Resources, Apr 2022]

SBK2 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=0.103370994).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SBK2	NM_001370096.2 link	c.914G>A	p.Arg305Gln	missense_variant	Exon 4 of 4	ENST00000413299.6	NP_001357025.1
SBK2	XM_011527227.3 link	c.*473G>A		3_prime_UTR_variant	Exon 4 of 4		XP_011525529.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SBK2	ENST00000413299.6 link	c.914G>A	p.Arg305Gln	missense_variant	Exon 4 of 4	5	NM_001370096.2	ENSP00000389015.2		P0C263
SBK2	ENST00000344158.4 link	c.914G>A	p.Arg305Gln	missense_variant	Exon 3 of 3	2		ENSP00000345044.3		P0C263

Frequencies

GnomAD3 genomes

AF:

0.0000329

AC:

AN:

152184

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000723

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000279

AC:

AN:

214778

Hom.:

AF XY:

0.0000334

AC XY:

AN XY:

119882

show subpopulations

Gnomad AFR exome

AF:

0.0000818

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:

0.0000533

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000387

AC:

AN:

1446170

Hom.:

Cov.:

AF XY:

0.0000306

AC XY:

AN XY:

719176

show subpopulations

Gnomad4 AFR exome

AF:

0.0000304

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000117

Gnomad4 FIN exome

AF:

0.0000219

Gnomad4 NFE exome

AF:

0.0000379

Gnomad4 OTH exome

AF:

0.000117

GnomAD4 genome

AF:

0.0000329

AC:

AN:

152184

Hom.:

Cov.:

AF XY:

0.0000538

AC XY:

AN XY:

74348

show subpopulations

Gnomad4 AFR

AF:

0.0000723

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000294

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000712

Hom.:

Bravo

AF:

0.0000264

ExAC

AF:

0.0000257

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

May 08, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.914G>A (p.R305Q) alteration is located in exon 4 (coding exon 3) of the SBK2 gene. This alteration results from a G to A substitution at nucleotide position 914, causing the arginine (R) at amino acid position 305 to be replaced by a glutamine (Q). 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

0.084

BayesDel_addAF

Benign

-0.29

BayesDel_noAF

Benign

-0.46

CADD

Benign

DANN

Uncertain

0.98

DEOGEN2

Benign

0.0036

T;T

Eigen

Benign

-0.66

Eigen_PC

Benign

-0.68

FATHMM_MKL

Benign

0.12

LIST_S2

Benign

0.26

T;.

M_CAP

Benign

0.046

MetaRNN

Benign

0.10

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.60

N;N

PrimateAI

Uncertain

0.58

PROVEAN

Benign

-0.21

N;N

REVEL

Benign

0.084

Sift

Benign

0.41

T;T

Sift4G

Benign

0.43

T;T

Polyphen

0.52

P;P

Vest4

0.14

MutPred

0.58

Loss of MoRF binding (P = 0.0491);Loss of MoRF binding (P = 0.0491);

MVP

0.48

MPC

1.1

ClinPred

0.058

GERP RS

1.7

Varity_R

0.046

gMVP

0.28

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

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