19-55304732-G-T

Variant names:

• chr19-55304732-G-T
• rs751535819
• NM_032430.2:c.1529G>T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_032430.2(BRSK1):​c.1529G>T​(p.Arg510Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000263 in 1,520,968 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 31)
  • Exomes 𝑓: 7.3e-7 (0 hom.)
• Consequence: BRSK1 NM_032430.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.72
• Publications: 0 publications found

Genes affected

BRSK1 (HGNC:18994): (BR serine/threonine kinase 1) Enables magnesium ion binding activity; protein serine/threonine kinase activity; and tau-protein kinase activity. Involved in mitotic G2 DNA damage checkpoint signaling and protein phosphorylation. Acts upstream of or within G2/M transition of mitotic cell cycle; peptidyl-serine phosphorylation; and response to UV. Located in cell junction; cytoplasm; and nucleoplasm. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.058342606).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BRSK1	NM_032430.2	c.1529G>T	p.Arg510Leu	missense_variant	Exon 14 of 19	ENST00000309383.6	NP_115806.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BRSK1	ENST00000309383.6	c.1529G>T	p.Arg510Leu	missense_variant	Exon 14 of 19	1	NM_032430.2	ENSP00000310649.1

Frequencies

GnomAD3 genomes AF: 0.0000199 AC: 3 AN: 150832 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.0000732

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: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00 AC: 0 AN: 118726 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 7.30e-7 AC: 1 AN: 1370136 Hom.: 0 Cov.: 35 AF XY: 0.00000148 AC XY: 1 AN XY: 676168

African (AFR) AF: 0.0000329 AC: 1 AN: 30354

American (AMR) AF: 0.00 AC: 0 AN: 32584

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23900

East Asian (EAS) AF: 0.00 AC: 0 AN: 35222

South Asian (SAS) AF: 0.00 AC: 0 AN: 77310

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 37360

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4012

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1072428

Other (OTH) AF: 0.00 AC: 0 AN: 56966

GnomAD4 genome AF: 0.0000199 AC: 3 AN: 150832 Hom.: 0 Cov.: 31 AF XY: 0.0000272 AC XY: 2 AN XY: 73624

African (AFR) AF: 0.0000732 AC: 3 AN: 40982

American (AMR) AF: 0.00 AC: 0 AN: 15158

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3456

East Asian (EAS) AF: 0.00 AC: 0 AN: 5128

South Asian (SAS) AF: 0.00 AC: 0 AN: 4766

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10382

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67668

Other (OTH) AF: 0.00 AC: 0 AN: 2076

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000113

ExAC AF: 0.0000101 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Apr 26, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1529G>T (p.R510L) alteration is located in exon 14 (coding exon 14) of the BRSK1 gene. This alteration results from a G to T substitution at nucleotide position 1529, causing the arginine (R) at amino acid position 510 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Benign	-0.51
CADD	Uncertain	24
DANN	Uncertain	0.98
DEOGEN2	Benign	0.058	.;T;T
Eigen	Benign	-0.43
Eigen_PC	Benign	-0.14
FATHMM_MKL	Benign	0.63	D
LIST_S2	Benign	0.77	T;T;T
M_CAP	Benign	0.018	T
MetaRNN	Benign	0.058	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-1.5	.;N;.
PhyloP100		1.7
PrimateAI	Pathogenic	0.82	D
PROVEAN	Benign	0.25	.;N;N
REVEL	Benign	0.057
Sift	Benign	0.43	.;T;T
Sift4G	Benign	0.58	T;T;T
Polyphen		0.0	B;B;.
Vest4		0.14
MutPred		0.36		.;Loss of methylation at R510 (P = 0.0365);.;
MVP		0.22
MPC		1.2
ClinPred		0.54	D
GERP RS		4.2
Varity_R		0.079
gMVP		0.10
Mutation Taster		=72/28	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: rs751535819; hg19: chr19-55816100;