11-1436103-G-A

Position:

• chr11-1436103-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_001256627.2(BRSK2):​c.155G>A​(p.Arg52His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000214 in 1,403,924 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 27)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: BRSK2 NM_001256627.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.34

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BRSK2	NM_001256627.2	c.155G>A	p.Arg52His	missense_variant	2/20	ENST00000528841.6	NP_001243556.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BRSK2	ENST00000528841.6	c.155G>A	p.Arg52His	missense_variant	2/20	1	NM_001256627.2	ENSP00000432000	P1

Frequencies

GnomAD3 genomes Cov.: 27

GnomAD4 exome AF: 0.00000214 AC: 3 AN: 1403924 Hom.: 0 Cov.: 31 AF XY: 0.00000287 AC XY: 2 AN XY: 697476

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0000207

Gnomad4 NFE exome AF: 0.00000186

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 27

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Mar 12, 2023

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.96
BayesDel_addAF	Uncertain	0.064	T
BayesDel_noAF	Benign	-0.15
CADD	Pathogenic	32
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.38	.;T;.;.;.
Eigen	Uncertain	0.47
Eigen_PC	Uncertain	0.35
FATHMM_MKL	Benign	0.71	D
LIST_S2	Pathogenic	0.99	D;D;D;D;D
M_CAP	Pathogenic	0.72	D
MetaRNN	Uncertain	0.69	D;D;D;D;D
MetaSVM	Benign	-0.30	T
MutationAssessor	Benign	1.9	L;L;L;L;.
MutationTaster	Benign	1.0	D;D;D;D;D;D;D
PrimateAI	Pathogenic	0.88	D
PROVEAN	Uncertain	-4.1	D;D;D;D;D
REVEL	Uncertain	0.54
Sift	Uncertain	0.0020	D;D;D;D;D
Sift4G	Uncertain	0.0020	D;D;D;D;D
Polyphen		1.0	D;D;D;D;D
Vest4		0.35
MutPred		0.78		Loss of MoRF binding (P = 0.025);Loss of MoRF binding (P = 0.025);Loss of MoRF binding (P = 0.025);Loss of MoRF binding (P = 0.025);.;
MVP		0.81
MPC		2.4
ClinPred		0.99	D
GERP RS		2.5
Varity_R		0.42
gMVP		0.68

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr11-1457333;