NM_173598.6:c.2711C>T

Variant names:

Variant summary

Our verdict is Benign. Variant got -11 ACMG points: 1P and 12B. PP3BP6_Very_StrongBS2

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 (★★).

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

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]

KSR2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -11 ACMG points.

PP3

Splicing scoreres supports a deletorius 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 [Likely_benign]. Clinvar id is 1587466.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS2

High AC in GnomAd4 at 217 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KSR2	NM_173598.6 link	c.2711C>T	p.Ser904Leu	missense_variant, splice_region_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
KSR2	ENST00000339824.7 link	c.2711C>T	p.Ser904Leu	missense_variant, splice_region_variant	Exon 18 of 20	5	NM_173598.6	ENSP00000339952.4		Q6VAB6-1

Frequencies

GnomAD3 genomes

AF:

0.00143

AC:

217

AN:

152194

Hom.:

Cov.:

show subpopulations

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

GnomAD3 exomes

AF:

0.00164

AC:

408

AN:

248960

Hom.:

AF XY:

0.00155

AC XY:

210

AN XY:

135070

show subpopulations

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 SAS exome

AF:

0.00

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.:

Cov.:

AF XY:

0.00151

AC XY:

1095

AN XY:

727010

show subpopulations

Gnomad4 AFR exome

AF:

0.000149

Gnomad4 AMR exome

AF:

0.000201

Gnomad4 ASJ exome

AF:

0.0301

Gnomad4 EAS exome

AF:

0.0000504

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.0000187

Gnomad4 NFE exome

AF:

0.00113

Gnomad4 OTH exome

AF:

0.00298

GnomAD4 genome

AF:

0.00142

AC:

217

AN:

152312

Hom.:

Cov.:

AF XY:

0.00126

AC XY:

AN XY:

74478

show subpopulations

Gnomad4 AFR

AF:

0.000265

Gnomad4 AMR

AF:

0.000523

Gnomad4 ASJ

AF:

0.0349

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00104

Gnomad4 OTH

AF:

0.00284

Alfa

AF:

0.00245

Hom.:

Bravo

AF:

0.00142

TwinsUK

AF:

0.00108

AC:

ALSPAC

AF:

0.000778

AC:

ESP6500AA

AF:

0.000789

AC:

ESP6500EA

AF:

0.00231

AC:

ExAC

AF:

0.00140

AC:

169

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Sep 10, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dec 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

KSR2: BS2 -

KSR2-related disorder

Benign:1

Jul 31, 2019

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.15

BayesDel_addAF

Benign

-0.26

BayesDel_noAF

Benign

-0.20

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.70

D;D

Eigen

Benign

0.010

Eigen_PC

Benign

0.18

FATHMM_MKL

Uncertain

0.91

LIST_S2

Uncertain

0.93

D;D

M_CAP

Benign

0.029

MetaRNN

Benign

0.0092

T;T

MetaSVM

Benign

-0.36

MutationAssessor

Benign

0.040

.;N

PrimateAI

Uncertain

0.77

PROVEAN

Uncertain

-2.8

D;D

REVEL

Uncertain

0.36

Sift

Benign

0.064

T;T

Sift4G

Uncertain

0.040

D;D

Polyphen

0.060

.;B

Vest4

0.35

MVP

0.58

MPC

0.65

ClinPred

0.043

GERP RS

4.9

Varity_R

0.60

gMVP

0.71

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over