11-1436103-G-C

Variant names:

• chr11-1436103-G-C
• rs2133007232
• NM_001256627.2:c.155G>C

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_001440669.1(BRSK2):​c.-26G>C variant causes a 5 prime UTR premature start codon gain change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 27)
• Consequence: BRSK2 NM_001440669.1 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.34
• 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 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.862

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001440669.1. 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.155G>C	p.Arg52Pro	missense	Exon 2 of 20	NP_001243556.1	Q8IWQ3-1
	BRSK2	NM_001440669.1		c.-26G>C		5_prime_UTR_premature_start_codon_gain	Exon 2 of 20	NP_001427598.1
	BRSK2	NM_001440671.1		c.-26G>C		5_prime_UTR_premature_start_codon_gain	Exon 2 of 21	NP_001427600.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BRSK2	ENST00000528841.6	TSL:1 MANE Select	c.155G>C	p.Arg52Pro	missense	Exon 2 of 20	ENSP00000432000.1	Q8IWQ3-1
	BRSK2	ENST00000526678.5	TSL:1	c.155G>C	p.Arg52Pro	missense	Exon 2 of 20	ENSP00000433370.1	Q8IWQ3-4
	BRSK2	ENST00000531197.5	TSL:1	c.155G>C	p.Arg52Pro	missense	Exon 2 of 20	ENSP00000431152.1	Q8IWQ3-2

Frequencies

GnomAD3 genomes Cov.: 27

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 27

ClinVar

ClinVar submissions

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
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Uncertain	0.11	D
BayesDel_noAF	Uncertain	-0.070
CADD	Pathogenic	30
DANN	Uncertain	1.0
DEOGEN2	Benign	0.40	T
Eigen	Uncertain	0.44
Eigen_PC	Uncertain	0.34
FATHMM_MKL	Uncertain	0.81	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Pathogenic	0.77	D
MetaRNN	Pathogenic	0.86	D
MetaSVM	Benign	-0.38	T
MutationAssessor	Benign	1.4	L
PhyloP100		9.3
PrimateAI	Pathogenic	0.89	D
PROVEAN	Pathogenic	-5.7	D
REVEL	Uncertain	0.56
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.0020	D
Polyphen		1.0	D
Vest4		0.56
MutPred		0.79		Loss of MoRF binding (P = 0.0077)
MVP		0.74
MPC		2.6
ClinPred		0.99	D
GERP RS		2.5
Varity_R		0.90
gMVP		0.92
Mutation Taster		=47/53	disease causing

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: rs2133007232; hg19: chr11-1457333;