12-117476593-C-T

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 1P and 5B. PP2 BP4 BS2

The NM_173598.6(KSR2):c.2453G>A(p.Arg818Gln) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.0000969 in 1,609,690 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R818W) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000098 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000097 (2 hom.)
• Consequence: KSR2 NM_173598.6 missense, splice_region
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.16

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]

ACMG classification

Verdict is Likely_benign. Variant got -4 ACMG points.

• PP2: Missense variant where missense usually causes diseases, KSR2
• BP4: Computational evidence support a benign effect (MetaRNN=0.41813836).
• BS2: High AC in GnomAd at 15 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KSR2	NM_173598.6	c.2453G>A	p.Arg818Gln	missense_variant, splice_region_variant	17/20	ENST00000339824.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KSR2	ENST00000339824.7	c.2453G>A	p.Arg818Gln	missense_variant, splice_region_variant	17/20	5	NM_173598.6	P1

Frequencies

GnomAD3 genomes AF: 0.0000985 AC: 15 AN: 152208 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00103

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000202 AC: 49 AN: 242480 Hom.: 1 AF XY: 0.000267 AC XY: 35 AN XY: 131234

Gnomad AFR exome AF: 0.0000663

Gnomad AMR exome AF: 0.000148

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000453

Gnomad SAS exome AF: 0.000930

Gnomad FIN exome AF: 0.0000472

Gnomad NFE exome AF: 0.0000454

Gnomad OTH exome AF: 0.000340

GnomAD4 exome AF: 0.0000967 AC: 141 AN: 1457364 Hom.: 2 Cov.: 30 AF XY: 0.000127 AC XY: 92 AN XY: 724500

Gnomad4 AFR exome AF: 0.0000599

Gnomad4 AMR exome AF: 0.000113

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000404

Gnomad4 SAS exome AF: 0.000707

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000441

Gnomad4 OTH exome AF: 0.000116

GnomAD4 genome AF: 0.0000985 AC: 15 AN: 152326 Hom.: 0 Cov.: 33 AF XY: 0.000121 AC XY: 9 AN XY: 74494

Gnomad4 AFR AF: 0.0000722

Gnomad4 AMR AF: 0.000196

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00104

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000441

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000892 Hom.: 0

Bravo AF: 0.0000491

ExAC AF: 0.000149 AC: 18

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

KSR2-related disorder Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Dec 07, 2023

The KSR2 c.2366G>A variant is predicted to result in the amino acid substitution p.Arg789Gln. This variant has been reported in multiple individuals of a family with severe early-onset obesity; however, additional affected family members did not carry this variant (described as c.2453G>A, p.R818Q in Pearce et al. 2013. PubMed ID: 24209692, see Figure 1A and Supplemental Table S1). In vitro studies suggested the p.Arg789Gln substitution may affect cellular signaling (Pearce et al. 2013. PubMed ID: 24209692). This variant is reported in 0.093% of alleles in individuals of South Asian descent in gnomAD (overall 51 of ~274,000 alleles) which may be too frequent to be a primary cause of disease. Although we suspect that this variant may be benign, 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	Benign	0.26
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Benign	-0.16
Cadd	Pathogenic	32
Dann	Uncertain	1.0
DEOGEN2	Uncertain	0.57	D;D
Eigen	Uncertain	0.31
Eigen_PC	Uncertain	0.34
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.91	D;D
M_CAP	Uncertain	0.16	D
MetaRNN	Benign	0.42	T;T
MetaSVM	Uncertain	-0.13	T
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.64	T
PROVEAN	Benign	-2.1	N;N
REVEL	Uncertain	0.55
Sift	Benign	0.089	T;T
Sift4G	Benign	0.15	T;T
Polyphen		1.0	.;D
Vest4		0.74
MutPred		0.50		.;Gain of catalytic residue at A815 (P = 0.0015);
MVP		0.81
MPC		1.7
ClinPred		0.16	T
GERP RS		4.8
Varity_R		0.71
gMVP		0.52

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.18		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: rs568149754; hg19: chr12-117914398; COSMIC: COSV56677433;