19-55289583-G-T

Position:

• chr19-55289583-G-T

Variant summary

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

The NM_032430.2(BRSK1):​c.421G>T​(p.Val141Leu) 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: 4.42

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=0.31653738).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BRSK1	NM_032430.2	c.421G>T	p.Val141Leu	missense_variant	4/19	ENST00000309383.6	NP_115806.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BRSK1	ENST00000309383.6	c.421G>T	p.Val141Leu	missense_variant	4/19	1	NM_032430.2	ENSP00000310649	P1
BRSK1	ENST00000590333.5	c.469G>T	p.Val157Leu	missense_variant	6/21	1		ENSP00000468190
BRSK1	ENST00000585418.1	c.421G>T	p.Val141Leu	missense_variant	4/10	1		ENSP00000467357
BRSK1	ENST00000592539.6	c.*166G>T		3_prime_UTR_variant, NMD_transcript_variant	5/7	5		ENSP00000466755

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

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

Oct 18, 2021

The c.421G>T (p.V141L) alteration is located in exon 4 (coding exon 4) of the BRSK1 gene. This alteration results from a G to T substitution at nucleotide position 421, causing the valine (V) at amino acid position 141 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	0.33
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Benign	-0.40
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.11	.;T;.
Eigen	Benign	-0.038
Eigen_PC	Benign	0.13
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Uncertain	0.94	D;D;D
M_CAP	Benign	0.025	T
MetaRNN	Benign	0.32	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.12	.;N;N
MutationTaster	Benign	0.94	D;D;D
PrimateAI	Uncertain	0.77	T
PROVEAN	Benign	-1.1	.;N;.
REVEL	Benign	0.14
Sift	Uncertain	0.0030	.;D;.
Sift4G	Uncertain	0.053	T;D;T
Polyphen		0.50	P;P;.
Vest4		0.59
MutPred		0.64		.;Loss of MoRF binding (P = 0.1219);Loss of MoRF binding (P = 0.1219);
MVP		0.47
MPC		1.6
ClinPred		0.79	D
GERP RS		5.3
Varity_R		0.23
gMVP		0.91

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr19-55800951;