rs1554904772

Variant names:

• chr11-1443490-G-A
• rs1554904772
• NM_001256627.2:c.635G>A

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PM2 PP3_Strong PP5_Moderate

The NM_001256627.2(BRSK2):​c.635G>A​(p.Gly212Glu) variant causes a missense, splice region 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. 14/24 in silico tools predict a damaging outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G212R) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: BRSK2 NM_001256627.2 missense, splice_region
• Scores: Splicing: ADA: 0.2603
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 9.49
• 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: Likely_pathogenic. The variant received 8 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.985
• PP5: Variant 11-1443490-G-A is Pathogenic according to our data. Variant chr11-1443490-G-A is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 517145.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001256627.2. 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.635G>A	p.Gly212Glu	missense splice_region	Exon 8 of 20	NP_001243556.1	Q8IWQ3-1
	BRSK2	NM_001440665.1		c.635G>A	p.Gly212Glu	missense splice_region	Exon 8 of 21	NP_001427594.1
	BRSK2	NM_001440666.1		c.635G>A	p.Gly212Glu	missense splice_region	Exon 8 of 20	NP_001427595.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BRSK2	ENST00000528841.6	TSL:1 MANE Select	c.635G>A	p.Gly212Glu	missense splice_region	Exon 8 of 20	ENSP00000432000.1	Q8IWQ3-1
	BRSK2	ENST00000526678.5	TSL:1	c.635G>A	p.Gly212Glu	missense splice_region	Exon 8 of 20	ENSP00000433370.1	Q8IWQ3-4
	BRSK2	ENST00000531197.5	TSL:1	c.635G>A	p.Gly212Glu	missense splice_region	Exon 8 of 20	ENSP00000431152.1	Q8IWQ3-2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

Significance: Likely pathogenic

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.32	D
BayesDel_noAF	Pathogenic	0.22
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.53	D
Eigen	Pathogenic	0.83
Eigen_PC	Uncertain	0.66
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Pathogenic	0.90	D
MetaRNN	Pathogenic	0.98	D
MetaSVM	Uncertain	0.23	D
MutationAssessor	Pathogenic	3.6	H
PhyloP100		9.5
PrimateAI	Pathogenic	0.93	D
PROVEAN	Pathogenic	-7.6	D
REVEL	Pathogenic	0.70
Sift	Uncertain	0.0010	D
Sift4G	Pathogenic	0.0010	D
Polyphen		0.99	D
Vest4		0.99
MutPred		0.82		Gain of solvent accessibility (P = 0.0789)
MVP		0.81
MPC		2.5
ClinPred		1.0	D
GERP RS		3.3
Varity_R		0.90
gMVP		0.98
Mutation Taster		=0/100	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.26
dbscSNV1_RF	Benign	0.45
SpliceAI score (max)		0.060		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: rs1554904772; hg19: chr11-1464720;