11-1436037-C-T

Position:

• chr11-1436037-C-T

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BS1 BS2

The NM_001256627.2(BRSK2):​c.92-3C>T variant causes a splice region, splice polypyrimidine tract, intron change. The variant allele was found at a frequency of 0.00115 in 1,603,538 control chromosomes in the GnomAD database, including 15 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00098 (0 hom., cov: 28)
  • Exomes 𝑓: 0.0012 (15 hom.)
• Consequence: BRSK2 NM_001256627.2 splice_region, splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.07717
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 5.49

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 Benign. Variant got -18 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.41).
• BP6: Variant 11-1436037-C-T is Benign according to our data. Variant chr11-1436037-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 720380.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.000976 (148/151610) while in subpopulation SAS AF= 0.00836 (40/4786). AF 95% confidence interval is 0.00631. There are 0 homozygotes in gnomad4. There are 73 alleles in male gnomad4 subpopulation. Median coverage is 28. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome4 at 15 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BRSK2	NM_001256627.2	c.92-3C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000528841.6	NP_001243556.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BRSK2	ENST00000528841.6	c.92-3C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_001256627.2	ENSP00000432000	P1

Frequencies

GnomAD3 genomes AF: 0.000984 AC: 149 AN: 151490 Hom.: 0 Cov.: 28

Gnomad AFR AF: 0.000170

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00256

Gnomad ASJ AF: 0.000577

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00835

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000766

Gnomad OTH AF: 0.00385

GnomAD3 exomes AF: 0.00191 AC: 454 AN: 237902 Hom.: 2 AF XY: 0.00240 AC XY: 311 AN XY: 129500

Gnomad AFR exome AF: 0.000140

Gnomad AMR exome AF: 0.00140

Gnomad ASJ exome AF: 0.000513

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00964

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000994

Gnomad OTH exome AF: 0.00225

GnomAD4 exome AF: 0.00116 AC: 1690 AN: 1451928 Hom.: 15 Cov.: 31 AF XY: 0.00145 AC XY: 1050 AN XY: 721754

Gnomad4 AFR exome AF: 0.000271

Gnomad4 AMR exome AF: 0.00171

Gnomad4 ASJ exome AF: 0.000232

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00981

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000540

Gnomad4 OTH exome AF: 0.00192

GnomAD4 genome AF: 0.000976 AC: 148 AN: 151610 Hom.: 0 Cov.: 28 AF XY: 0.000986 AC XY: 73 AN XY: 74072

Gnomad4 AFR AF: 0.000169

Gnomad4 AMR AF: 0.00249

Gnomad4 ASJ AF: 0.000577

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00836

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000766

Gnomad4 OTH AF: 0.00381

Alfa AF: 0.000884 Hom.: 0

Bravo AF: 0.00105

Asia WGS AF: 0.00375 AC: 13 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	May 08, 2018	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2024	BRSK2: BP4, BS2 -

BRSK2-related disorder Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 17, 2022

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.41
CADD	Benign	14
DANN	Benign	0.87

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.077
dbscSNV1_RF	Benign	0.34
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

LitVar

Other links and lift over

dbSNP: rs200299640; hg19: chr11-1457267;