19-55301537-A-C

Variant names:

• chr19-55301537-A-C
• rs1600184700
• NM_032430.2:c.704A>C

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_032430.2(BRSK1):​c.704A>C​(p.Asn235Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N235S) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: BRSK1 NM_032430.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 9.06
• 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: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BRSK1	NM_032430.2	c.704A>C	p.Asn235Thr	missense_variant	Exon 8 of 19	ENST00000309383.6	NP_115806.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BRSK1	ENST00000309383.6	c.704A>C	p.Asn235Thr	missense_variant	Exon 8 of 19	1	NM_032430.2	ENSP00000310649.1
BRSK1	ENST00000590333.5	c.752A>C	p.Asn251Thr	missense_variant	Exon 10 of 21	1		ENSP00000468190.1
BRSK1	ENST00000585418.1	c.704A>C	p.Asn235Thr	missense_variant	Exon 8 of 10	1		ENSP00000467357.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Benign	-0.056	T
BayesDel_noAF	Benign	-0.32
CADD	Pathogenic	27
DANN	Uncertain	0.99
DEOGEN2	Benign	0.32	.;T;.
Eigen	Uncertain	0.43
Eigen_PC	Uncertain	0.48
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Uncertain	0.94	D;D;D
M_CAP	Benign	0.018	T
MetaRNN	Uncertain	0.69	D;D;D
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.3	.;L;L
PhyloP100		9.1
PrimateAI	Pathogenic	0.80	T
PROVEAN	Pathogenic	-5.6	.;D;.
REVEL	Benign	0.28
Sift	Uncertain	0.016	.;D;.
Sift4G	Uncertain	0.013	D;D;T
Polyphen		0.89	P;P;.
Vest4		0.83
MutPred		0.51		.;Gain of phosphorylation at N235 (P = 0.0596);Gain of phosphorylation at N235 (P = 0.0596);
MVP		0.52
MPC		2.0
ClinPred		0.99	D
GERP RS		4.6
Varity_R		0.71
gMVP		0.92
Mutation Taster		=28/72	disease causing

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: rs1600184700; hg19: chr19-55812905;