11-1390303-G-C

Variant names:

• chr11-1390303-G-C
• rs533360037
• NM_001256627.2:c.19G>C

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 2P and 6B. PM2 BP4_Moderate BS1

The NM_001256627.2(BRSK2):​c.19G>C​(p.Asp7His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000136 in 147,210 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/18 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.000014 (0 hom., cov: 32)
• Consequence: BRSK2 NM_001256627.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.72

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 Likely_benign. Variant got -4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.13973188).
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.0000136 (2/147210) while in subpopulation SAS AF= 0.000415 (2/4824). AF 95% confidence interval is 0.000073. There are 0 homozygotes in gnomad4. There are 1 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BRSK2	NM_001256627.2	c.19G>C	p.Asp7His	missense_variant	Exon 1 of 20	ENST00000528841.6	NP_001243556.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BRSK2	ENST00000528841.6	c.19G>C	p.Asp7His	missense_variant	Exon 1 of 20	1	NM_001256627.2	ENSP00000432000.1

Frequencies

GnomAD3 genomes AF: 0.0000136 AC: 2 AN: 147126 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: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 32

GnomAD4 genome AF: 0.0000136 AC: 2 AN: 147210 Hom.: 0 Cov.: 32 AF XY: 0.0000139 AC XY: 1 AN XY: 71704

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000415

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.41
BayesDel_addAF	Benign	-0.10	T
BayesDel_noAF	Benign	-0.38
CADD	Uncertain	24
DANN	Benign	0.95
DEOGEN2	Benign	0.15	.;T;.;.
Eigen	Benign	-0.32
Eigen_PC	Benign	-0.27
FATHMM_MKL	Benign	0.69	D
LIST_S2	Benign	0.79	T;T;T;T
M_CAP	Pathogenic	0.58	D
MetaRNN	Benign	0.14	T;T;T;T
MetaSVM	Benign	-0.86	T
MutationAssessor	Benign	0.34	N;N;N;N
PROVEAN	Benign	-0.49	N;N;N;N
REVEL	Benign	0.094
Sift	Benign	0.060	T;D;T;D
Sift4G	Benign	0.11	T;T;T;T
Polyphen		0.76	P;B;B;P
Vest4		0.089
MutPred		0.22		Gain of MoRF binding (P = 0.0526);Gain of MoRF binding (P = 0.0526);Gain of MoRF binding (P = 0.0526);Gain of MoRF binding (P = 0.0526);
MVP		0.58
ClinPred		0.15	T
GERP RS		1.6
Varity_R		0.12

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

LitVar

Other links and lift over

dbSNP: rs533360037; hg19: chr11-1411533;