19-55302756-T-C

Position:

• chr19-55302756-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_032430.2(BRSK1):​c.917T>C​(p.Met306Thr) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: BRSK1 NM_032430.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.08

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

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.37593782).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BRSK1	NM_032430.2	c.917T>C	p.Met306Thr	missense_variant	10/19	ENST00000309383.6	NP_115806.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BRSK1	ENST00000309383.6	c.917T>C	p.Met306Thr	missense_variant	10/19	1	NM_032430.2	ENSP00000310649	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

May 29, 2024

The c.917T>C (p.M306T) alteration is located in exon 10 (coding exon 10) of the BRSK1 gene. This alteration results from a T to C substitution at nucleotide position 917, causing the methionine (M) at amino acid position 306 to be replaced by a threonine (T). 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	Uncertain	0.46
BayesDel_addAF	Uncertain	0.054	T
BayesDel_noAF	Benign	-0.16
CADD	Uncertain	24
DANN	Uncertain	0.98
DEOGEN2	Benign	0.052	.;T;.;.;T
Eigen	Benign	-0.25
Eigen_PC	Benign	-0.036
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.77	T;T;T;D;D
M_CAP	Benign	0.015	T
MetaRNN	Benign	0.20	T;T;T;T;T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	-0.69	.;N;N;.;.
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Pathogenic	0.85	D
PROVEAN	Benign	1.2	.;N;.;.;N
REVEL	Benign	0.15
Sift	Benign	0.89	.;T;.;.;D
Sift4G	Benign	1.0	T;T;T;D;D
Polyphen		0.019	B;B;.;.;.
Vest4		0.45
MutPred		0.33		.;Gain of phosphorylation at M306 (P = 0.0165);Gain of phosphorylation at M306 (P = 0.0165);.;.;
MVP		0.92
MPC		0.95
ClinPred		0.83	D
GERP RS		4.7
Varity_R		0.17
gMVP		0.89

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: rs2088590892; hg19: chr19-55814124;