chr19-55529804-C-T

Variant names:

• chr19-55529804-C-T
• NM_001370096.2:c.976G>A

Variant summary

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

The NM_001370096.2(SBK2):​c.976G>A​(p.Gly326Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000413 in 1,452,222 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000041 (0 hom.)
• Consequence: SBK2 NM_001370096.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.422

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 rank	MANE	Protein	UniProt
SBK2	NM_001370096.2	c.976G>A	p.Gly326Arg	missense_variant	Exon 4 of 4	ENST00000413299.6	NP_001357025.1
SBK2	XM_011527227.3	c.*535G>A		3_prime_UTR_variant	Exon 4 of 4		XP_011525529.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SBK2	ENST00000413299.6	c.976G>A	p.Gly326Arg	missense_variant	Exon 4 of 4	5	NM_001370096.2	ENSP00000389015.2
SBK2	ENST00000344158.4	c.976G>A	p.Gly326Arg	missense_variant	Exon 3 of 3	2		ENSP00000345044.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000413 AC: 6 AN: 1452222 Hom.: 0 Cov.: 34 AF XY: 0.00000415 AC XY: 3 AN XY: 722870

Gnomad4 AFR exome AF: 0.00

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: 0.00000540

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jun 07, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.976G>A (p.G326R) alteration is located in exon 4 (coding exon 3) of the SBK2 gene. This alteration results from a G to A substitution at nucleotide position 976, causing the glycine (G) at amino acid position 326 to be replaced by an arginine (R). 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	0.21
BayesDel_addAF	Benign	-0.030	T
BayesDel_noAF	Benign	-0.28
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.020	T;T
Eigen	Benign	-0.10
Eigen_PC	Benign	-0.19
FATHMM_MKL	Benign	0.39	N
LIST_S2	Benign	0.67	T;.
M_CAP	Uncertain	0.25	D
MetaRNN	Uncertain	0.60	D;D
MetaSVM	Benign	-0.65	T
MutationAssessor	Benign	1.3	L;L
PrimateAI	Uncertain	0.56	T
PROVEAN	Uncertain	-2.5	N;N
REVEL	Benign	0.27
Sift	Benign	0.11	T;T
Sift4G	Uncertain	0.042	D;D
Polyphen		0.99	D;D
Vest4		0.53
MutPred		0.28		Gain of MoRF binding (P = 0.0301);Gain of MoRF binding (P = 0.0301);
MVP		0.64
MPC		2.3
ClinPred		0.92	D
GERP RS		3.9
Varity_R		0.12
gMVP		0.62

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: chr19-56041171; COSMIC: COSV60013920;