11-1390303-G-A

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4_StrongBS1_Supporting

The NM_001256627.2(BRSK2):c.19G>A(p.Asp7Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000356 in 1,039,550 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: 𝑓 0.000075 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000029 ( 0 hom. )

Consequence

BRSK2
NM_001256627.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 1.72

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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -5 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.03531742).

BS1

Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.0000747 (11/147210) while in subpopulation EAS AF = 0.00137 (7/5094). AF 95% confidence interval is 0.000645. There are 0 homozygotes in GnomAd4. There are 1 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position FAILED quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BRSK2	NM_001256627.2 link	c.19G>A	p.Asp7Asn	missense_variant	Exon 1 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.19G>A	p.Asp7Asn	missense_variant	Exon 1 of 20	1	NM_001256627.2	ENSP00000432000.1		Q8IWQ3-1

Frequencies

GnomAD3 genomes

AF:

0.0000748

AC:

AN:

147126

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000674

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00137

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00148

GnomAD2 exomes

AF:

0.00

AC:

AN:

30640

AF XY:

0.00

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 FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000291

AC:

AN:

892340

Hom.:

Cov.:

AF XY:

0.0000192

AC XY:

AN XY:

416464

show subpopulations

Gnomad4 AFR exome

AF:

0.00

AC:

AN:

17000

Gnomad4 AMR exome

AF:

0.00

AC:

AN:

3754

Gnomad4 ASJ exome

AF:

0.00

AC:

AN:

6200

Gnomad4 EAS exome

AF:

0.000676

AC:

AN:

7396

Gnomad4 SAS exome

AF:

0.00

AC:

AN:

18502

Gnomad4 FIN exome

AF:

0.00

AC:

AN:

17342

Gnomad4 NFE exome

AF:

0.00000633

AC:

AN:

789628

Gnomad4 Remaining exome

AF:

0.000539

AC:

AN:

29702

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

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

AF:

0.0000747

AC:

AN:

147210

Hom.:

Cov.:

AF XY:

0.0000139

AC XY:

AN XY:

71704

show subpopulations

Gnomad4 AFR

AF:

0.00

AC:

AN:

Gnomad4 AMR

AF:

0.0000673

AC:

0.0000673491

AN:

0.0000673491

Gnomad4 ASJ

AF:

0.00

AC:

AN:

Gnomad4 EAS

AF:

0.00137

AC:

0.00137417

AN:

0.00137417

Gnomad4 SAS

AF:

0.00

AC:

AN:

Gnomad4 FIN

AF:

0.00

AC:

AN:

Gnomad4 NFE

AF:

0.00

AC:

AN:

Gnomad4 OTH

AF:

0.00146

AC:

0.00146199

AN:

0.00146199

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Genome 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

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000680

ExAC

AF:

0.0000193

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Inborn genetic diseases

Uncertain:1

Feb 28, 2023

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.19G>A (p.D7N) alteration is located in exon 1 (coding exon 1) of the BRSK2 gene. This alteration results from a G to A substitution at nucleotide position 19, causing the aspartic acid (D) at amino acid position 7 to be replaced by an asparagine (N). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

BRSK2-related disorder

Uncertain:1

Aug 18, 2022

PreventionGenetics, part of Exact Sciences

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The BRSK2 c.19G>A variant is predicted to result in the amino acid substitution p.Asp7Asn. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.032% of alleles in individuals of East Asian descent in gnomAD (http://gnomad.broadinstitute.org/variant/11-1411533-G-A). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.17

BayesDel_addAF

Benign

-0.17

BayesDel_noAF

Benign

-0.48

CADD

Uncertain

DANN

Uncertain

0.99

DEOGEN2

Benign

0.10

.;T;.;.

Eigen

Benign

-0.52

Eigen_PC

Benign

-0.42

FATHMM_MKL

Benign

0.70

LIST_S2

Benign

0.80

T;T;T;T

M_CAP

Pathogenic

0.50

MetaRNN

Benign

0.035

T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

-1.0

N;N;N;N

PROVEAN

Benign

0.51

N;N;N;N

REVEL

Benign

0.049

Sift

Benign

0.40

T;T;T;T

Sift4G

Benign

0.48

T;T;T;T

Polyphen

0.13

B;B;B;B

Vest4

0.082

MutPred

0.22

Gain of MoRF binding (P = 0.0319);Gain of MoRF binding (P = 0.0319);Gain of MoRF binding (P = 0.0319);Gain of MoRF binding (P = 0.0319);

MVP

0.52

ClinPred

0.13

GERP RS

1.6

Varity_R

0.089

Mutation Taster

=94/6

polymorphism

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

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