Genetic Variant BRSK2:c.91+21070G>T (chr11-1411445-G-T) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_001256630.1(BRSK2):c.41G>T(p.Arg14Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000152 in 1,315,142 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R14H) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000015 ( 0 hom. )

Consequence

BRSK2
NM_001256630.1 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -1.50

Publications

0 publications found

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 Gene-Disease associations (from GenCC):

complex neurodevelopmental disorder
Inheritance: AD Classification: DEFINITIVE, MODERATE Submitted by: ClinGen, Ambry Genetics
neurodevelopmental disorder
Inheritance: AD Classification: STRONG Submitted by: G2P
autosomal dominant non-syndromic intellectual disability
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

BRSK2 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.076567054).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001256630.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
BRSK2	NM_001256627.2	MANE Select	c.91+21070G>T		intron	N/A	NP_001243556.1	Q8IWQ3-1
BRSK2	NM_001256630.1		c.41G>T	p.Arg14Leu	missense	Exon 1 of 20	NP_001243559.1	Q8IWQ3-5
BRSK2	NM_001440667.1		c.41G>T	p.Arg14Leu	missense	Exon 1 of 20	NP_001427596.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
BRSK2	ENST00000528841.6	TSL:1 MANE Select	c.91+21070G>T	intron	N/A	ENSP00000432000.1	Q8IWQ3-1
BRSK2	ENST00000526678.5	TSL:1	c.91+21070G>T	intron	N/A	ENSP00000433370.1	Q8IWQ3-4
BRSK2	ENST00000531197.5	TSL:1	c.91+21070G>T	intron	N/A	ENSP00000431152.1	Q8IWQ3-2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000152

AC:

AN:

1315142

Hom.:

Cov.:

AF XY:

0.00000156

AC XY:

AN XY:

642856

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

26918

American (AMR)

AF:

0.00

AC:

AN:

24858

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

18832

East Asian (EAS)

AF:

0.00

AC:

AN:

33612

South Asian (SAS)

AF:

0.00

AC:

AN:

67450

European-Finnish (FIN)

AF:

0.00

AC:

AN:

34064

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5188

European-Non Finnish (NFE)

AF:

0.00000191

AC:

AN:

1049768

Other (OTH)

AF:

0.00

AC:

AN:

54452

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.00000037155), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.325

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Benign

-0.21

BayesDel_noAF

Benign

-0.54

CADD

Benign

2.4

(source)

DANN

Uncertain

0.99

Eigen

Benign

-1.1

Eigen_PC

Benign

-1.2

FATHMM_MKL

Benign

0.047

LIST_S2

Benign

0.31

M_CAP

Benign

0.032

MetaRNN

Benign

0.077

MetaSVM

Benign

-1.0

PhyloP100

-1.5

PrimateAI

Benign

0.39

PROVEAN

Benign

-0.14

REVEL

Benign

0.011

Sift

Pathogenic

0.0

Sift4G

Benign

0.31

Polyphen

0.026

Vest4

0.19

MutPred

0.28

Loss of solvent accessibility (P = 0.0022)

MVP

0.30

MPC

0.037

ClinPred

0.17

GERP RS

0.80

PromoterAI

0.0062

Neutral

(source)

gMVP

0.30

Mutation Taster

=97/3

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over