chr11-1390309-G-A

Variant names:

• chr11-1390309-G-A
• rs897841626
• NM_001256627.2:c.25G>A

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_001256627.2(BRSK2):​c.25G>A​(p.Gly9Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000115 in 1,044,462 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 0.000014 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000011 (0 hom.)
• Consequence: BRSK2 NM_001256627.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.0300
• Publications: 1 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_benign. The variant received -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.09467688).
• BS2: High AC in GnomAdExome4 at 10 AD gene.

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.25G>A	p.Gly9Ser	missense	Exon 1 of 20	NP_001243556.1	Q8IWQ3-1
	BRSK2	NM_001440665.1		c.25G>A	p.Gly9Ser	missense	Exon 1 of 21	NP_001427594.1
	BRSK2	NM_001440666.1		c.25G>A	p.Gly9Ser	missense	Exon 1 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.25G>A	p.Gly9Ser	missense	Exon 1 of 20	ENSP00000432000.1	Q8IWQ3-1
	BRSK2	ENST00000526678.5	TSL:1	c.25G>A	p.Gly9Ser	missense	Exon 1 of 20	ENSP00000433370.1	Q8IWQ3-4
	BRSK2	ENST00000531197.5	TSL:1	c.25G>A	p.Gly9Ser	missense	Exon 1 of 20	ENSP00000431152.1	Q8IWQ3-2

Frequencies

GnomAD3 genomes AF: 0.0000136 AC: 2 AN: 147118 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

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: 0.0000303

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.0000111 AC: 10 AN: 897344 Hom.: 0 Cov.: 32 AF XY: 0.00000955 AC XY: 4 AN XY: 419066

African (AFR) AF: 0.00 AC: 0 AN: 17112

American (AMR) AF: 0.00 AC: 0 AN: 4072

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 6288

East Asian (EAS) AF: 0.00 AC: 0 AN: 7910

South Asian (SAS) AF: 0.00 AC: 0 AN: 18622

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 17906

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2848

European-Non Finnish (NFE) AF: 0.0000114 AC: 9 AN: 792622

Other (OTH) AF: 0.0000334 AC: 1 AN: 29964

GnomAD4 genome AF: 0.0000136 AC: 2 AN: 147118 Hom.: 0 Cov.: 32 AF XY: 0.0000279 AC XY: 2 AN XY: 71586

African (AFR) AF: 0.00 AC: 0 AN: 40974

American (AMR) AF: 0.00 AC: 0 AN: 14830

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3398

East Asian (EAS) AF: 0.00 AC: 0 AN: 5094

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

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 8622

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 312

European-Non Finnish (NFE) AF: 0.0000303 AC: 2 AN: 66112

Other (OTH) AF: 0.00 AC: 0 AN: 2032

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.082
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Benign	-0.55
CADD	Uncertain	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.10	T
Eigen	Benign	-0.63
Eigen_PC	Benign	-0.53
FATHMM_MKL	Benign	0.11	N
LIST_S2	Benign	0.58	T
M_CAP	Pathogenic	0.45	D
MetaRNN	Benign	0.095	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.13	N
PhyloP100		0.030
PROVEAN	Benign	0.54	N
REVEL	Benign	0.059
Sift	Benign	0.12	T
Sift4G	Benign	0.68	T
Polyphen		0.0	B
Vest4		0.084
MutPred		0.20		Gain of glycosylation at G9 (P = 0.1346)
MVP		0.51
ClinPred		0.28	T
GERP RS		0.57
PromoterAI		-0.030	Neutral
Varity_R		0.086
Mutation Taster		=91/9	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs897841626; hg19: chr11-1411539;