rs1013100859

Variant names:

• chr11-1411617-G-GCAGCC
• rs1013100859
• NM_001256627.2:c.91+21252_91+21256dupCCAGC

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 8P and 5B. PVS1 BS1_Supporting BS2

The NM_001256630.1(BRSK2):​c.223_227dupCCAGC​(p.Gly77GlnfsTer5) variant causes a frameshift, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000179 in 1,561,476 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 34)
  • Exomes 𝑓: 0.000018 (0 hom.)
• Consequence: BRSK2 NM_001256630.1 frameshift, splice_region
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.29
• Publications: 0 publications found

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

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• BS1: Variant frequency is greater than expected in population afr. GnomAdExome4 allele frequency = 0.0000177 (25/1409142) while in subpopulation AFR AF = 0.000124 (4/32168). AF 95% confidence interval is 0.000042. There are 0 homozygotes in GnomAdExome4. There are 15 alleles in the male GnomAdExome4 subpopulation. Median coverage is 34. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High AC in GnomAdExome4 at 25 AD gene.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BRSK2	NM_001256627.2	MANE Select	c.91+21252_91+21256dupCCAGC		intron	N/A	NP_001243556.1	Q8IWQ3-1
	BRSK2	NM_001256630.1		c.223_227dupCCAGC	p.Gly77GlnfsTer5	frameshift splice_region	Exon 1 of 20	NP_001243559.1	Q8IWQ3-5
	BRSK2	NM_001440667.1		c.223_227dupCCAGC	p.Gly77GlnfsTer5	frameshift splice_region	Exon 1 of 20	NP_001427596.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BRSK2	ENST00000528841.6	TSL:1 MANE Select	c.91+21252_91+21256dupCCAGC		intron	N/A	ENSP00000432000.1	Q8IWQ3-1
	BRSK2	ENST00000526678.5	TSL:1	c.91+21252_91+21256dupCCAGC		intron	N/A	ENSP00000433370.1	Q8IWQ3-4
	BRSK2	ENST00000531197.5	TSL:1	c.91+21252_91+21256dupCCAGC		intron	N/A	ENSP00000431152.1	Q8IWQ3-2

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152216 Hom.: 0 Cov.: 34

Gnomad AFR AF: 0.0000241

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: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.0000177 AC: 25 AN: 1409142 Hom.: 0 Cov.: 34 AF XY: 0.0000215 AC XY: 15 AN XY: 698608

African (AFR) AF: 0.000124 AC: 4 AN: 32168

American (AMR) AF: 0.00 AC: 0 AN: 39326

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25284

East Asian (EAS) AF: 0.00 AC: 0 AN: 37238

South Asian (SAS) AF: 0.0000122 AC: 1 AN: 82156

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 35322

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4942

European-Non Finnish (NFE) AF: 9.14e-7 AC: 1 AN: 1094032

Other (OTH) AF: 0.000324 AC: 19 AN: 58674

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 152334 Hom.: 0 Cov.: 34 AF XY: 0.0000268 AC XY: 2 AN XY: 74488

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

African (AFR) AF: 0.0000721 AC: 3 AN: 41588

American (AMR) AF: 0.00 AC: 0 AN: 15314

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5166

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68022

Other (OTH) AF: 0.00 AC: 0 AN: 2114

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

Asia WGS AF: 0.00115 AC: 4 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		3.3
Mutation Taster		=29/171	disease causing (fs/PTC)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs1013100859; hg19: chr11-1432847;