rs61868960

Variant names:

• chr11-1411461-T-C
• rs61868960
• NM_001256627.2:c.91+21086T>C

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6 BP7 BA1

The NM_001256630.1(BRSK2):​c.57T>C​(p.Cys19Cys) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.464 in 1,470,786 control chromosomes in the GnomAD database, including 166,451 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (no stars).

• Frequency:
  • Genomes: 𝑓 0.43 (14851 hom., cov: 34)
  • Exomes 𝑓: 0.47 (151600 hom.)
• Consequence: BRSK2 NM_001256630.1 synonymous
• Clinical Significance: Benign no assertion criteria provided B:1
• Conservation: PhyloP100: 0.0120
• Publications: 7 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: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-1.05).
• BP6: Variant 11-1411461-T-C is Benign according to our data. Variant chr11-1411461-T-C is described in ClinVar as Benign. ClinVar VariationId is 3059255.Status of the report is no_assertion_criteria_provided, 0 stars.
• BP7: Synonymous conserved (PhyloP=0.012 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.491 is higher than 0.05.

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+21086T>C		intron	N/A	NP_001243556.1	Q8IWQ3-1
	BRSK2	NM_001256630.1		c.57T>C	p.Cys19Cys	synonymous	Exon 1 of 20	NP_001243559.1	Q8IWQ3-5
	BRSK2	NM_001440667.1		c.57T>C	p.Cys19Cys	synonymous	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+21086T>C		intron	N/A	ENSP00000432000.1	Q8IWQ3-1
	BRSK2	ENST00000526678.5	TSL:1	c.91+21086T>C		intron	N/A	ENSP00000433370.1	Q8IWQ3-4
	BRSK2	ENST00000531197.5	TSL:1	c.91+21086T>C		intron	N/A	ENSP00000431152.1	Q8IWQ3-2

Frequencies

GnomAD3 genomes AF: 0.428 AC: 65119 AN: 152078 Hom.: 14840 Cov.: 34

Gnomad AFR AF: 0.379

Gnomad AMI AF: 0.618

Gnomad AMR AF: 0.375

Gnomad ASJ AF: 0.401

Gnomad EAS AF: 0.0204

Gnomad SAS AF: 0.245

Gnomad FIN AF: 0.551

Gnomad MID AF: 0.297

Gnomad NFE AF: 0.495

Gnomad OTH AF: 0.404

GnomAD2 exomes AF: 0.396 AC: 49994 AN: 126252 AF XY: 0.403

Gnomad AFR exome AF: 0.369

Gnomad AMR exome AF: 0.309

Gnomad ASJ exome AF: 0.437

Gnomad EAS exome AF: 0.0118

Gnomad FIN exome AF: 0.536

Gnomad NFE exome AF: 0.496

Gnomad OTH exome AF: 0.432

GnomAD4 exome AF: 0.468 AC: 616859 AN: 1318590 Hom.: 151600 Cov.: 55 AF XY: 0.463 AC XY: 298314 AN XY: 644582

African (AFR) AF: 0.374 AC: 10177 AN: 27176

American (AMR) AF: 0.320 AC: 8181 AN: 25538

Ashkenazi Jewish (ASJ) AF: 0.418 AC: 7919 AN: 18950

East Asian (EAS) AF: 0.0160 AC: 549 AN: 34318

South Asian (SAS) AF: 0.263 AC: 17941 AN: 68140

European-Finnish (FIN) AF: 0.534 AC: 18203 AN: 34072

Middle Eastern (MID) AF: 0.336 AC: 1742 AN: 5192

European-Non Finnish (NFE) AF: 0.503 AC: 528214 AN: 1050624

Other (OTH) AF: 0.438 AC: 23933 AN: 54580

GnomAD4 genome AF: 0.428 AC: 65181 AN: 152196 Hom.: 14851 Cov.: 34 AF XY: 0.423 AC XY: 31503 AN XY: 74402

African (AFR) AF: 0.379 AC: 15753 AN: 41530

American (AMR) AF: 0.374 AC: 5731 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.401 AC: 1393 AN: 3470

East Asian (EAS) AF: 0.0209 AC: 108 AN: 5176

South Asian (SAS) AF: 0.246 AC: 1186 AN: 4830

European-Finnish (FIN) AF: 0.551 AC: 5838 AN: 10604

Middle Eastern (MID) AF: 0.293 AC: 86 AN: 294

European-Non Finnish (NFE) AF: 0.495 AC: 33668 AN: 67958

Other (OTH) AF: 0.404 AC: 854 AN: 2112

Alfa AF: 0.452 Hom.: 2259

Bravo AF: 0.412

Asia WGS AF: 0.146 AC: 511 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
-	-	1	BRSK2-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.1
CADD	Benign	4.7
DANN	Benign	0.44
PhyloP100		0.012
PromoterAI		0.026	Neutral
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs61868960; hg19: chr11-1432691; COSMIC: COSV57543988;