8-66840018-C-A

Variant summary

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

The NM_001033578.3(SGK3):​c.757C>A​(p.Gln253Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000186 in 1,611,716 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 31)
Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

SGK3
NM_001033578.3 missense

Scores

3
7
8

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.84
Variant links:
Genes affected
SGK3 (HGNC:10812): (serum/glucocorticoid regulated kinase family member 3) This gene is a member of the Ser/Thr protein kinase family and encodes a phosphoprotein with a PX (phox homology) domain. The protein phosphorylates several target proteins and has a role in neutral amino acid transport and activation of potassium and chloride channels. Alternate transcriptional splice variants, encoding different isoforms, have been characterized. [provided by RefSeq, Jul 2008]
C8orf44-SGK3 (HGNC:48354): (C8orf44-SGK3 readthrough) This locus represents naturally occurring read-through transcription between the neighboring putative uncharacterized protein C8orf44 (GeneID 56260) and serine/threonine-protein kinase Sgk3 (GeneID 23678) genes on chromosome 8. The read-through transcript produces a protein that shares sequence identity with the downstream gene product. [provided by RefSeq, Feb 2011]

Genome browser will be placed here

ACMG classification

Classification made for transcript

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
SGK3NM_001033578.3 linkc.757C>A p.Gln253Lys missense_variant Exon 11 of 17 ENST00000521198.7 NP_001028750.1 Q96BR1-1A0A024R807Q5H9Q5
C8orf44-SGK3NM_001204173.2 linkc.757C>A p.Gln253Lys missense_variant Exon 13 of 19 NP_001191102.1 Q96BR1-1A0A024R807
SGK3NM_013257.5 linkc.757C>A p.Gln253Lys missense_variant Exon 11 of 17 NP_037389.4 Q96BR1-1A0A024R807Q53EW6Q5H9Q5
SGK3NM_170709.3 linkc.757C>A p.Gln253Lys missense_variant Exon 11 of 16 NP_733827.2 Q96BR1-2Q53EW6Q5H9Q5

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
SGK3ENST00000521198.7 linkc.757C>A p.Gln253Lys missense_variant Exon 11 of 17 1 NM_001033578.3 ENSP00000430463.1 Q96BR1-1
C8orf44-SGK3ENST00000519289.1 linkc.757C>A p.Gln253Lys missense_variant Exon 13 of 19 2 ENSP00000429022.1

Frequencies

GnomAD3 genomes
AF:
0.00000658
AC:
1
AN:
151994
Hom.:
0
Cov.:
31
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.0000655
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:
0.00
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.00000398
AC:
1
AN:
251104
Hom.:
0
AF XY:
0.00
AC XY:
0
AN XY:
135696
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.0000545
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000137
AC:
2
AN:
1459722
Hom.:
0
Cov.:
32
AF XY:
0.00000138
AC XY:
1
AN XY:
726154
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.0000253
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
9.00e-7
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.00000658
AC:
1
AN:
151994
Hom.:
0
Cov.:
31
AF XY:
0.00
AC XY:
0
AN XY:
74242
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.0000655
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.00000756

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Jul 14, 2024
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.757C>A (p.Q253K) alteration is located in exon 11 (coding exon 10) of the SGK3 gene. This alteration results from a C to A substitution at nucleotide position 757, causing the glutamine (Q) at amino acid position 253 to be replaced by a lysine (K). 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
Pathogenic
0.90
BayesDel_addAF
Benign
-0.031
T
BayesDel_noAF
Benign
-0.11
CADD
Pathogenic
28
DANN
Uncertain
0.99
DEOGEN2
Benign
0.35
T;T;T;T;.;T;T
Eigen
Uncertain
0.47
Eigen_PC
Uncertain
0.47
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Uncertain
0.93
.;.;D;.;D;.;D
M_CAP
Benign
0.039
D
MetaRNN
Uncertain
0.69
D;D;D;D;D;D;D
MetaSVM
Benign
-0.44
T
MutationAssessor
Benign
0.36
N;N;N;N;N;N;.
PrimateAI
Pathogenic
0.84
D
PROVEAN
Uncertain
-3.9
D;D;D;D;D;D;D
REVEL
Uncertain
0.42
Sift
Benign
0.10
T;T;T;T;T;T;D
Sift4G
Benign
0.11
T;T;T;T;T;T;T
Polyphen
1.0
D;D;D;D;D;D;.
Vest4
0.91
MutPred
0.64
Gain of methylation at Q253 (P = 0.0285);Gain of methylation at Q253 (P = 0.0285);Gain of methylation at Q253 (P = 0.0285);Gain of methylation at Q253 (P = 0.0285);Gain of methylation at Q253 (P = 0.0285);Gain of methylation at Q253 (P = 0.0285);.;
MVP
0.69
MPC
0.51
ClinPred
0.73
D
GERP RS
5.3
Varity_R
0.81
gMVP
0.64

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.12
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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs778801923; hg19: chr8-67752253; API