chr12-117469644-T-C

Variant names:

• chr12-117469644-T-C
• rs12304889
• NM_173598.6:c.2846+18A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong 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, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.281
• Publications: 6 publications found

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

Our verdict: Benign. The variant received -20 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 VariationId is 1599375.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.234 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_173598.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KSR2	NM_173598.6	MANE Select	c.2846+18A>G		intron	N/A	NP_775869.4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KSR2	ENST00000339824.7	TSL:5 MANE Select	c.2846+18A>G		intron	N/A	ENSP00000339952.4	Q6VAB6-1

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

GnomAD2 exomes AF: 0.137 AC: 33096 AN: 242362 AF XY: 0.135

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 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

African (AFR) AF: 0.240 AC: 8031 AN: 33420

American (AMR) AF: 0.0951 AC: 4201 AN: 44192

Ashkenazi Jewish (ASJ) AF: 0.0840 AC: 2191 AN: 26068

East Asian (EAS) AF: 0.162 AC: 6395 AN: 39592

South Asian (SAS) AF: 0.0973 AC: 8283 AN: 85144

European-Finnish (FIN) AF: 0.179 AC: 9510 AN: 53184

Middle Eastern (MID) AF: 0.114 AC: 656 AN: 5764

European-Non Finnish (NFE) AF: 0.131 AC: 145612 AN: 1109548

Other (OTH) AF: 0.136 AC: 8185 AN: 60246

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

African (AFR) AF: 0.238 AC: 9840 AN: 41370

American (AMR) AF: 0.108 AC: 1649 AN: 15264

Ashkenazi Jewish (ASJ) AF: 0.0804 AC: 279 AN: 3468

East Asian (EAS) AF: 0.192 AC: 989 AN: 5152

South Asian (SAS) AF: 0.106 AC: 509 AN: 4810

European-Finnish (FIN) AF: 0.186 AC: 1961 AN: 10562

Middle Eastern (MID) AF: 0.122 AC: 36 AN: 294

European-Non Finnish (NFE) AF: 0.129 AC: 8736 AN: 67924

Other (OTH) AF: 0.131 AC: 276 AN: 2110

Alfa AF: 0.138 Hom.: 2422

Bravo AF: 0.159

Asia WGS AF: 0.148 AC: 516 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	4.5
DANN	Benign	0.60
PhyloP100		-0.28
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

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