19-55530011-G-A

Position:

• chr19-55530011-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_001370096.2(SBK2):​c.769C>T​(p.Leu257Phe) variant causes a missense change. The variant allele was found at a frequency of 0.000000732 in 1,365,212 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.3e-7 (0 hom.)
• Consequence: SBK2 NM_001370096.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.25

Genes affected

SBK2 (HGNC:34416): (SH3 domain binding kinase family member 2) Predicted to enable MAP kinase kinase activity. Predicted to be involved in MAPK cascade and protein phosphorylation. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SBK2	NM_001370096.2	c.769C>T	p.Leu257Phe	missense_variant	4/4	ENST00000413299.6
SBK2	XM_011527227.3	c.*328C>T		3_prime_UTR_variant	4/4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SBK2	ENST00000413299.6	c.769C>T	p.Leu257Phe	missense_variant	4/4	5	NM_001370096.2	P1
SBK2	ENST00000344158.4	c.769C>T	p.Leu257Phe	missense_variant	3/3	2		P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 7.32e-7 AC: 1 AN: 1365212 Hom.: 0 Cov.: 34 AF XY: 0.00000149 AC XY: 1 AN XY: 672714

Gnomad4 AFR exome AF: 0.0000344

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000756

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

Aug 26, 2022

The c.769C>T (p.L257F) alteration is located in exon 4 (coding exon 3) of the SBK2 gene. This alteration results from a C to T substitution at nucleotide position 769, causing the leucine (L) at amino acid position 257 to be replaced by a phenylalanine (F). 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	0.36
BayesDel_addAF	Uncertain	0.079	D
BayesDel_noAF	Benign	-0.12
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Benign	0.072	T;T
Eigen	Uncertain	0.66
Eigen_PC	Uncertain	0.56
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.88	D;.
M_CAP	Uncertain	0.12	D
MetaRNN	Uncertain	0.54	D;D
MetaSVM	Benign	-0.41	T
MutationAssessor	Uncertain	2.5	M;M
MutationTaster	Benign	1.0	D;D
PrimateAI	Pathogenic	0.84	D
PROVEAN	Uncertain	-2.9	D;D
REVEL	Uncertain	0.35
Sift	Uncertain	0.0040	D;D
Sift4G	Uncertain	0.022	D;D
Polyphen		1.0	D;D
Vest4		0.51
MutPred		0.46		Gain of catalytic residue at L257 (P = 0.1492);Gain of catalytic residue at L257 (P = 0.1492);
MVP		0.78
MPC		2.2
ClinPred		0.97	D
GERP RS		4.0
Varity_R		0.22
gMVP		0.61

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: rs1427609372; hg19: chr19-56041378;