12-117469644-T-C

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_173598.6(KSR2):c.2846+18A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.135 in 1,609,024 control chromosomes in the GnomAD database, including 15,836 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.16 (2193 hom., cov: 32)
  • Exomes 𝑓: 0.13 (13643 hom.)
• Consequence: KSR2 NM_173598.6 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.281

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 Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BP6: Variant 12-117469644-T-C is Benign according to our data. Variant chr12-117469644-T-C is described in ClinVar as [Benign]. Clinvar id is 1599375.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.234 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KSR2	NM_173598.6	c.2846+18A>G		intron_variant		ENST00000339824.7
KSR2	XM_011538224.4	c.2840+18A>G		intron_variant
KSR2	XM_011538225.4	c.2483+18A>G		intron_variant
KSR2	XM_017019210.3	c.1541+18A>G		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KSR2	ENST00000339824.7	c.2846+18A>G		intron_variant		5	NM_173598.6	P1

Frequencies

GnomAD3 genomes AF: 0.161 AC: 24378 AN: 151746 Hom.: 2194 Cov.: 32

Gnomad AFR AF: 0.238

Gnomad AMI AF: 0.138

Gnomad AMR AF: 0.108

Gnomad ASJ AF: 0.0804

Gnomad EAS AF: 0.192

Gnomad SAS AF: 0.105

Gnomad FIN AF: 0.186

Gnomad MID AF: 0.127

Gnomad NFE AF: 0.129

Gnomad OTH AF: 0.133

GnomAD3 exomes AF: 0.137 AC: 33096 AN: 242362 Hom.: 2532 AF XY: 0.135 AC XY: 17649 AN XY: 131136

Gnomad AFR exome AF: 0.234

Gnomad AMR exome AF: 0.0950

Gnomad ASJ exome AF: 0.0878

Gnomad EAS exome AF: 0.201

Gnomad SAS exome AF: 0.0961

Gnomad FIN exome AF: 0.182

Gnomad NFE exome AF: 0.133

Gnomad OTH exome AF: 0.126

GnomAD4 exome AF: 0.132 AC: 193064 AN: 1457158 Hom.: 13643 Cov.: 32 AF XY: 0.131 AC XY: 95106 AN XY: 724250

Gnomad4 AFR exome AF: 0.240

Gnomad4 AMR exome AF: 0.0951

Gnomad4 ASJ exome AF: 0.0840

Gnomad4 EAS exome AF: 0.162

Gnomad4 SAS exome AF: 0.0973

Gnomad4 FIN exome AF: 0.179

Gnomad4 NFE exome AF: 0.131

Gnomad4 OTH exome AF: 0.136

GnomAD4 genome AF: 0.161 AC: 24401 AN: 151866 Hom.: 2193 Cov.: 32 AF XY: 0.162 AC XY: 12022 AN XY: 74244

Gnomad4 AFR AF: 0.238

Gnomad4 AMR AF: 0.108

Gnomad4 ASJ AF: 0.0804

Gnomad4 EAS AF: 0.192

Gnomad4 SAS AF: 0.106

Gnomad4 FIN AF: 0.186

Gnomad4 NFE AF: 0.129

Gnomad4 OTH AF: 0.131

Alfa AF: 0.134 Hom.: 1555

Bravo AF: 0.159

Asia WGS AF: 0.148 AC: 516 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
Cadd	Benign	4.5
Dann	Benign	0.60

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

Other links and lift over

dbSNP: rs12304889; hg19: chr12-117907449; COSMIC: COSV56682899;