chr19-55304611-T-G

Variant names:

• chr19-55304611-T-G
• rs747737039
• NM_032430.2:c.1408T>G

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_032430.2(BRSK1):​c.1408T>G​(p.Ser470Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000103 in 1,560,404 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 31)
  • Exomes 𝑓: 0.000011 (0 hom.)
• Consequence: BRSK1 NM_032430.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.706
• 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 -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.09892559).
• BS2: High AC in GnomAdExome4 at 15 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BRSK1	NM_032430.2	c.1408T>G	p.Ser470Ala	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.1408T>G	p.Ser470Ala	missense_variant	Exon 14 of 19	1	NM_032430.2	ENSP00000310649.1

Frequencies

GnomAD3 genomes AF: 0.00000659 AC: 1 AN: 151842 Hom.: 0 Cov.: 31

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: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000186 AC: 3 AN: 161312 AF XY: 0.0000224

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: 0.0000447

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000106 AC: 15 AN: 1408562 Hom.: 0 Cov.: 36 AF XY: 0.0000115 AC XY: 8 AN XY: 697692

African (AFR) AF: 0.00 AC: 0 AN: 30644

American (AMR) AF: 0.00 AC: 0 AN: 36570

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24096

East Asian (EAS) AF: 0.00 AC: 0 AN: 38134

South Asian (SAS) AF: 0.00 AC: 0 AN: 79880

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 48970

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4760

European-Non Finnish (NFE) AF: 0.0000138 AC: 15 AN: 1087548

Other (OTH) AF: 0.00 AC: 0 AN: 57960

GnomAD4 genome AF: 0.00000659 AC: 1 AN: 151842 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 74158

African (AFR) AF: 0.00 AC: 0 AN: 41316

American (AMR) AF: 0.00 AC: 0 AN: 15256

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5156

South Asian (SAS) AF: 0.00 AC: 0 AN: 4798

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10608

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 67922

Other (OTH) AF: 0.00 AC: 0 AN: 2088

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000264

ExAC AF: 0.0000170 AC: 2

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Mar 06, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1408T>G (p.S470A) alteration is located in exon 14 (coding exon 14) of the BRSK1 gene. This alteration results from a T to G substitution at nucleotide position 1408, causing the serine (S) at amino acid position 470 to be replaced by an alanine (A). 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	0.069
BayesDel_addAF	Benign	-0.30	T
BayesDel_noAF	Benign	-0.54
CADD	Benign	22
DANN	Uncertain	0.97
DEOGEN2	Benign	0.077	.;T;T
Eigen	Benign	-0.44
Eigen_PC	Benign	-0.21
FATHMM_MKL	Benign	0.75	D
LIST_S2	Benign	0.45	T;T;T
M_CAP	Benign	0.014	T
MetaRNN	Benign	0.099	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	-0.20	.;N;.
PhyloP100		0.71
PrimateAI	Pathogenic	0.81	D
PROVEAN	Benign	-0.63	.;N;N
REVEL	Benign	0.039
Sift	Benign	0.27	.;T;T
Sift4G	Benign	0.47	T;T;T
Polyphen		0.042	B;B;.
Vest4		0.14
MVP		0.46
MPC		0.74
ClinPred		0.064	T
GERP RS		3.8
Varity_R		0.054
gMVP		0.072
Mutation Taster		=65/35	polymorphism

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

Other links and lift over

dbSNP: rs747737039; hg19: chr19-55815979;