Genetic Variant BRSK1:p.Arg498Ser (chr19-55304695-C-A) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 4P and 2B. PM1PM2BP4_Moderate

The NM_032430.2(BRSK1):c.1492C>A(p.Arg498Ser) variant causes a missense change. The variant allele was found at a frequency of 0.000000751 in 1,331,416 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 31)

Exomes 𝑓: 7.5e-7 ( 0 hom. )

Consequence

BRSK1
NM_032430.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 6.44

Publications

0 publications found

Variant links:

Genes affected

BRSK1 (HGNC:18994): (BR serine/threonine kinase 1) Enables magnesium ion binding activity; protein serine/threonine kinase activity; and tau-protein kinase activity. Involved in mitotic G2 DNA damage checkpoint signaling and protein phosphorylation. Acts upstream of or within G2/M transition of mitotic cell cycle; peptidyl-serine phosphorylation; and response to UV. Located in cell junction; cytoplasm; and nucleoplasm. [provided by Alliance of Genome Resources, Apr 2022]

BRSK1 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM1

In a modified_residue Omega-N-methylarginine (size 0) in uniprot entity BRSK1_HUMAN

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.16827047).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BRSK1	NM_032430.2 link	c.1492C>A	p.Arg498Ser	missense_variant	Exon 14 of 19	ENST00000309383.6	NP_115806.1	Q8TDC3-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BRSK1	ENST00000309383.6 link	c.1492C>A	p.Arg498Ser	missense_variant	Exon 14 of 19	1	NM_032430.2	ENSP00000310649.1		Q8TDC3-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

7.51e-7

AC:

AN:

1331416

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

654680

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

28156

American (AMR)

AF:

0.00

AC:

AN:

24740

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

20998

East Asian (EAS)

AF:

0.00

AC:

AN:

34704

South Asian (SAS)

AF:

0.00

AC:

AN:

70066

European-Finnish (FIN)

AF:

0.00

AC:

AN:

36474

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3838

European-Non Finnish (NFE)

AF:

9.46e-7

AC:

AN:

1057230

Other (OTH)

AF:

0.00

AC:

AN:

55210

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

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

Jul 20, 2022

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.1492C>A (p.R498S) alteration is located in exon 14 (coding exon 14) of the BRSK1 gene. This alteration results from a C to A substitution at nucleotide position 1492, causing the arginine (R) at amino acid position 498 to be replaced by a serine (S). 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

0.23

BayesDel_addAF

Benign

-0.14

BayesDel_noAF

Benign

-0.44

CADD

Pathogenic

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.088

.;T;T

Eigen

Benign

-0.22

Eigen_PC

Benign

0.00013

FATHMM_MKL

Uncertain

0.87

LIST_S2

Benign

0.84

T;T;D

M_CAP

Benign

0.013

MetaRNN

Benign

0.17

T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.20

.;N;.

PhyloP100

6.4

PrimateAI

Uncertain

0.77

PROVEAN

Benign

-0.91

.;N;N

REVEL

Benign

0.058

Sift

Benign

0.086

.;T;T

Sift4G

Benign

0.32

T;T;T

Polyphen

0.0020

B;B;.

Vest4

0.29

MutPred

0.40

.;Gain of phosphorylation at R498 (P = 0.0022);.;

MVP

0.44

MPC

1.3

ClinPred

0.77

GERP RS

3.9

Varity_R

0.15

gMVP

0.19

Mutation Taster

=85/15

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.16

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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19-55304695-C-A

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over