chr12-117471192-G-A

Variant names:

• chr12-117471192-G-A
• rs201637020
• NM_173598.6:c.2711C>T

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 1P and 12B. PP3 BP6_Very_Strong BS2

The NM_173598.6(KSR2):​c.2711C>T​(p.Ser904Leu) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00152 in 1,613,770 control chromosomes in the GnomAD database, including 18 homozygotes. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. S904S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0014 (6 hom., cov: 32)
  • Exomes 𝑓: 0.0015 (12 hom.)
• Consequence: KSR2 NM_173598.6 missense, splice_region
• Scores: Splicing: ADA: 0.9918
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 2.85
• Publications: 7 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 -11 ACMG points.

• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.
• BP6: Variant 12-117471192-G-A is Benign according to our data. Variant chr12-117471192-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 1587466.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomAd4 at 217 AD gene.

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.2711C>T	p.Ser904Leu	missense splice_region	Exon 18 of 20	NP_775869.4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KSR2	ENST00000339824.7	TSL:5 MANE Select	c.2711C>T	p.Ser904Leu	missense splice_region	Exon 18 of 20	ENSP00000339952.4	Q6VAB6-1

Frequencies

GnomAD3 genomes AF: 0.00143 AC: 217 AN: 152194 Hom.: 6 Cov.: 32

Gnomad AFR AF: 0.000265

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000524

Gnomad ASJ AF: 0.0349

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00104

Gnomad OTH AF: 0.00287

GnomAD2 exomes AF: 0.00164 AC: 408 AN: 248960 AF XY: 0.00155

Gnomad AFR exome AF: 0.000258

Gnomad AMR exome AF: 0.0000580

Gnomad ASJ exome AF: 0.0277

Gnomad EAS exome AF: 0.0000557

Gnomad FIN exome AF: 0.0000465

Gnomad NFE exome AF: 0.000939

Gnomad OTH exome AF: 0.00248

GnomAD4 exome AF: 0.00153 AC: 2240 AN: 1461458 Hom.: 12 Cov.: 30 AF XY: 0.00151 AC XY: 1095 AN XY: 727010

African (AFR) AF: 0.000149 AC: 5 AN: 33476

American (AMR) AF: 0.000201 AC: 9 AN: 44710

Ashkenazi Jewish (ASJ) AF: 0.0301 AC: 787 AN: 26120

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39690

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86222

European-Finnish (FIN) AF: 0.0000187 AC: 1 AN: 53388

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00113 AC: 1255 AN: 1111722

Other (OTH) AF: 0.00298 AC: 180 AN: 60362

GnomAD4 genome AF: 0.00142 AC: 217 AN: 152312 Hom.: 6 Cov.: 32 AF XY: 0.00126 AC XY: 94 AN XY: 74478

African (AFR) AF: 0.000265 AC: 11 AN: 41580

American (AMR) AF: 0.000523 AC: 8 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.0349 AC: 121 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.00 AC: 0 AN: 4820

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10608

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00104 AC: 71 AN: 68026

Other (OTH) AF: 0.00284 AC: 6 AN: 2114

Alfa AF: 0.00218 Hom.: 5

Bravo AF: 0.00142

TwinsUK AF: 0.00108 AC: 4

ALSPAC AF: 0.000778 AC: 3

ESP6500AA AF: 0.000789 AC: 3

ESP6500EA AF: 0.00231 AC: 19

ExAC AF: 0.00140 AC: 169

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	KSR2-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Benign	-0.20
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.70	D
Eigen	Benign	0.010
Eigen_PC	Benign	0.18
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Uncertain	0.93	D
M_CAP	Benign	0.029	D
MetaRNN	Benign	0.0092	T
MetaSVM	Benign	-0.36	T
MutationAssessor	Benign	0.040	N
PhyloP100		2.8
PrimateAI	Uncertain	0.77	T
PROVEAN	Uncertain	-2.8	D
REVEL	Uncertain	0.36
Sift	Benign	0.064	T
Sift4G	Uncertain	0.040	D
Polyphen		0.060	B
Vest4		0.35
MVP		0.58
MPC		0.65
ClinPred		0.043	T
GERP RS		4.9
Varity_R		0.60
gMVP		0.71
Mutation Taster		=66/34	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	0.99
dbscSNV1_RF	Pathogenic	0.74
SpliceAI score (max)		0.11		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: rs201637020; hg19: chr12-117908997; COSMIC: COSV56675444;