12-117471298-C-T

Variant summary

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

The NM_173598.6(KSR2):​c.2605G>A​(p.Ala869Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000958 in 1,461,376 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: 0.0000096 ( 0 hom. )

Consequence

KSR2
NM_173598.6 missense

Scores

3
11
5

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]

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -3 ACMG points.

PP3
MetaRNN computational evidence supports a deleterious effect, 0.776
BS2
High AC in GnomAdExome4 at 14 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
KSR2NM_173598.6 linkc.2605G>A p.Ala869Thr missense_variant Exon 18 of 20 ENST00000339824.7 NP_775869.4 Q6VAB6-1E9PB13

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
KSR2ENST00000339824.7 linkc.2605G>A p.Ala869Thr missense_variant Exon 18 of 20 5 NM_173598.6 ENSP00000339952.4 Q6VAB6-1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD3 exomes
AF:
0.00000402
AC:
1
AN:
248886
Hom.:
0
AF XY:
0.00000741
AC XY:
1
AN XY:
135034
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.0000464
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000958
AC:
14
AN:
1461376
Hom.:
0
Cov.:
30
AF XY:
0.00000688
AC XY:
5
AN XY:
726972
show subpopulations
Gnomad4 AFR exome
AF:
0.0000299
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:
0.0000562
Gnomad4 NFE exome
AF:
0.00000900
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
32
Bravo
AF:
0.00000378
ExAC
AF:
0.00000826
AC:
1

ClinVar

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

Submissions by phenotype

not specified Uncertain:1
Dec 17, 2024
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.2518G>A (p.A840T) alteration is located in exon 18 (coding exon 18) of the KSR2 gene. This alteration results from a G to A substitution at nucleotide position 2518, causing the alanine (A) at amino acid position 840 to be replaced by a threonine (T). 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
0.34
BayesDel_addAF
Pathogenic
0.21
D
BayesDel_noAF
Uncertain
0.060
CADD
Pathogenic
27
DANN
Uncertain
1.0
DEOGEN2
Uncertain
0.57
D;D
Eigen
Uncertain
0.26
Eigen_PC
Uncertain
0.38
FATHMM_MKL
Uncertain
0.94
D
LIST_S2
Uncertain
0.96
D;D
M_CAP
Uncertain
0.19
D
MetaRNN
Pathogenic
0.78
D;D
MetaSVM
Uncertain
-0.19
T
MutationAssessor
Benign
-1.1
.;N
PrimateAI
Pathogenic
0.87
D
PROVEAN
Benign
-1.9
N;N
REVEL
Uncertain
0.64
Sift
Uncertain
0.025
D;D
Sift4G
Benign
0.063
T;T
Polyphen
0.98
.;D
Vest4
0.85
MutPred
0.57
.;Gain of catalytic residue at W864 (P = 0);
MVP
0.90
MPC
1.1
ClinPred
0.90
D
GERP RS
4.6
Varity_R
0.48
gMVP
0.59

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.13
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: rs757146540; hg19: chr12-117909103; COSMIC: COSV100196512; API