Genetic Variant BRSK2:p.Ser56Asn (chr11-1436115-G-A) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4

The NM_001256627.2(BRSK2):c.167G>A(p.Ser56Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000669 in 149,586 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: 𝑓 0.0000067 ( 0 hom., cov: 26)

Consequence

BRSK2
NM_001256627.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.60

Variant links:

Genes affected

BRSK2 (HGNC:11405): (BR serine/threonine kinase 2) Enables several functions, including ATP binding activity; ATPase binding activity; and protein kinase activity. Involved in several processes, including cellular protein metabolic process; intrinsic apoptotic signaling pathway in response to endoplasmic reticulum stress; and regulation of insulin secretion involved in cellular response to glucose stimulus. Located in centrosome and endoplasmic reticulum. [provided by Alliance of Genome Resources, Apr 2022]

BRSK2 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.34133938).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BRSK2	NM_001256627.2 link	c.167G>A	p.Ser56Asn	missense_variant	Exon 2 of 20	ENST00000528841.6	NP_001243556.1	Q8IWQ3-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BRSK2	ENST00000528841.6 link	c.167G>A	p.Ser56Asn	missense_variant	Exon 2 of 20	1	NM_001256627.2	ENSP00000432000.1		Q8IWQ3-1

Frequencies

GnomAD3 genomes

AF:

0.00000669

AC:

AN:

149586

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

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:

0.0000148

Gnomad OTH

AF:

0.00

GnomAD4 exome

Cov.:

GnomAD4 genome

AF:

0.00000669

AC:

AN:

149586

Hom.:

Cov.:

AF XY:

0.0000137

AC XY:

AN XY:

72888

show subpopulations

Gnomad4 AFR

AF:

0.00

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:

0.0000148

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000224

Hom.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Uncertain:1

Mar 08, 2024

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.89

BayesDel_addAF

Benign

-0.15

BayesDel_noAF

Benign

-0.45

CADD

Uncertain

DANN

Uncertain

0.99

DEOGEN2

Benign

0.25

.;T;.;.;.

Eigen

Benign

-0.037

Eigen_PC

Benign

-0.11

FATHMM_MKL

Benign

0.69

LIST_S2

Pathogenic

0.97

D;D;D;D;D

M_CAP

Uncertain

0.16

MetaRNN

Benign

0.34

T;T;T;T;T

MetaSVM

Benign

-0.82

MutationAssessor

Benign

0.56

N;N;N;N;.

PrimateAI

Pathogenic

0.86

PROVEAN

Uncertain

-2.6

D;D;D;D;D

REVEL

Benign

0.18

Sift

Benign

0.18

T;T;T;T;T

Sift4G

Benign

0.17

T;T;T;T;T

Polyphen

0.99

D;P;P;D;D

Vest4

0.34

MutPred

0.32

Gain of ubiquitination at K54 (P = 0.0605);Gain of ubiquitination at K54 (P = 0.0605);Gain of ubiquitination at K54 (P = 0.0605);Gain of ubiquitination at K54 (P = 0.0605);.;

MVP

0.74

MPC

1.2

ClinPred

0.89

GERP RS

1.6

Varity_R

0.23

gMVP

0.60

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