chr11-1436121-C-A

Variant names:

• chr11-1436121-C-A
• NM_001256627.2:c.173C>A

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1 PM2 PP3_Moderate

The NM_001256627.2(BRSK2):​c.173C>A​(p.Ser58*) variant causes a stop gained change. The variant allele was found at a frequency of 0.000000835 in 1,198,024 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 25)
  • Exomes 𝑓: 8.3e-7 (0 hom.)
• Consequence: BRSK2 NM_001256627.2 stop_gained
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.56

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 Pathogenic. Variant got 12 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BRSK2	NM_001256627.2	c.173C>A	p.Ser58*	stop_gained	Exon 2 of 20	ENST00000528841.6	NP_001243556.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BRSK2	ENST00000528841.6	c.173C>A	p.Ser58*	stop_gained	Exon 2 of 20	1	NM_001256627.2	ENSP00000432000.1

Frequencies

GnomAD3 genomes Cov.: 25

GnomAD4 exome AF: 8.35e-7 AC: 1 AN: 1198024 Hom.: 0 Cov.: 29 AF XY: 0.00000168 AC XY: 1 AN XY: 594056

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: 0.0000126

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 25

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.55	D
BayesDel_noAF	Pathogenic	0.55
CADD	Pathogenic	58
DANN	Uncertain	0.99
Eigen	Uncertain	0.49
Eigen_PC	Uncertain	0.26
FATHMM_MKL	Uncertain	0.84	D
Vest4		0.82
GERP RS		2.5

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.96		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.96		Position offset: -3

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: chr11-1457351;