chr12-117469698-C-T

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 1P and 4B. PP3BS2

The NM_173598.6(KSR2):​c.2810G>A​(p.Arg937His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000616 in 1,460,996 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)
Exomes 𝑓: 0.0000062 ( 0 hom. )

Consequence

KSR2
NM_173598.6 missense

Scores

6
11
2

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.91
Variant links:
Genes affected
KSR2 (HGNC:18610): (kinase suppressor of ras 2) Predicted to enable MAP-kinase scaffold activity; mitogen-activated protein kinase kinase binding activity; and protein kinase activity. Predicted to be involved in Ras protein signal transduction; calcium-mediated signaling; and positive regulation of cold-induced thermogenesis. Predicted to act upstream of or within positive regulation of MAPK cascade. Predicted to be active in cytosol and plasma membrane. [provided by Alliance of Genome Resources, Apr 2022]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -3 ACMG points.

PP3
MetaRNN computational evidence supports a deleterious effect, 0.819
BS2
High AC in GnomAdExome4 at 9 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
KSR2NM_173598.6 linkuse as main transcriptc.2810G>A p.Arg937His missense_variant 19/20 ENST00000339824.7
KSR2XM_011538224.4 linkuse as main transcriptc.2804G>A p.Arg935His missense_variant 19/20
KSR2XM_011538225.4 linkuse as main transcriptc.2447G>A p.Arg816His missense_variant 19/20
KSR2XM_017019210.3 linkuse as main transcriptc.1505G>A p.Arg502His missense_variant 14/15

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
KSR2ENST00000339824.7 linkuse as main transcriptc.2810G>A p.Arg937His missense_variant 19/205 NM_173598.6 P1Q6VAB6-1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
AF:
0.00000616
AC:
9
AN:
1460996
Hom.:
0
Cov.:
32
AF XY:
0.00000413
AC XY:
3
AN XY:
726668
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000810
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
32
Bravo
AF:
0.0000113

ClinVar

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

Submissions by phenotype

KSR2-related disorder Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingPreventionGenetics, part of Exact SciencesSep 01, 2023The KSR2 c.2723G>A variant is predicted to result in the amino acid substitution p.Arg908His. To our knowledge, this variant has not been reported in the literature or in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.99
BayesDel_addAF
Pathogenic
0.23
D
BayesDel_noAF
Uncertain
0.090
CADD
Pathogenic
33
DANN
Uncertain
1.0
DEOGEN2
Benign
0.35
T;T
Eigen
Uncertain
0.45
Eigen_PC
Uncertain
0.36
FATHMM_MKL
Pathogenic
0.98
D
LIST_S2
Uncertain
0.97
D;D
M_CAP
Uncertain
0.24
D
MetaRNN
Pathogenic
0.82
D;D
MetaSVM
Uncertain
0.25
D
MutationAssessor
Uncertain
2.6
.;M
MutationTaster
Benign
1.0
D;D
PrimateAI
Pathogenic
0.85
D
PROVEAN
Uncertain
-2.7
D;D
REVEL
Pathogenic
0.71
Sift
Uncertain
0.0090
D;D
Sift4G
Uncertain
0.016
D;D
Polyphen
1.0
.;D
Vest4
0.80
MutPred
0.37
.;Loss of MoRF binding (P = 0.0143);
MVP
0.86
MPC
1.9
ClinPred
0.99
D
GERP RS
3.7
Varity_R
0.35
gMVP
0.44

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

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

Other links and lift over

dbSNP: rs34526243; hg19: chr12-117907503; COSMIC: COSV56674372; API