12-117469751-A-G

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2

The NM_173598.6(KSR2):c.2757T>C(p.Pro919=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00135 in 1,613,944 control chromosomes in the GnomAD database, including 29 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.0069 ( 16 hom., cov: 32)

Exomes 𝑓: 0.00077 ( 13 hom. )

Consequence

KSR2
NM_173598.6 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: -0.0200

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 -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.53).

BP6

Variant 12-117469751-A-G is Benign according to our data. Variant chr12-117469751-A-G is described in ClinVar as [Benign]. Clinvar id is 768590.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-0.02 with no splicing effect.

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00688 (1048/152344) while in subpopulation AFR AF= 0.0234 (974/41568). AF 95% confidence interval is 0.0222. There are 16 homozygotes in gnomad4. There are 488 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High AC in GnomAd at 1034 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
KSR2	NM_173598.6 linkuse as main transcript	c.2757T>C	p.Pro919=	synonymous_variant	19/20	ENST00000339824.7
KSR2	XM_011538224.4 linkuse as main transcript	c.2751T>C	p.Pro917=	synonymous_variant	19/20
KSR2	XM_011538225.4 linkuse as main transcript	c.2394T>C	p.Pro798=	synonymous_variant	19/20
KSR2	XM_017019210.3 linkuse as main transcript	c.1452T>C	p.Pro484=	synonymous_variant	14/15

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KSR2	ENST00000339824.7 linkuse as main transcript	c.2757T>C	p.Pro919=	synonymous_variant	19/20	5	NM_173598.6	P1	Q6VAB6-1

Frequencies

GnomAD3 genomes

AF:

0.00679

AC:

1034

AN:

152226

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0232

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00393

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000735

Gnomad OTH

AF:

0.00382

GnomAD3 exomes

AF:

0.00171

AC:

427

AN:

249044

Hom.:

AF XY:

0.00137

AC XY:

185

AN XY:

135086

show subpopulations

Gnomad AFR exome

AF:

0.0241

Gnomad AMR exome

AF:

0.00104

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000983

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000531

Gnomad OTH exome

AF:

0.00149

GnomAD4 exome

AF:

0.000771

AC:

1127

AN:

1461600

Hom.:

Cov.:

AF XY:

0.000682

AC XY:

496

AN XY:

727062

show subpopulations

Gnomad4 AFR exome

AF:

0.0254

Gnomad4 AMR exome

AF:

0.00139

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000468

Gnomad4 OTH exome

AF:

0.00219

GnomAD4 genome

AF:

0.00688

AC:

1048

AN:

152344

Hom.:

Cov.:

AF XY:

0.00655

AC XY:

488

AN XY:

74510

show subpopulations

Gnomad4 AFR

AF:

0.0234

Gnomad4 AMR

AF:

0.00392

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000735

Gnomad4 OTH

AF:

0.00378

Alfa

AF:

0.00339

Hom.:

Bravo

AF:

0.00767

Asia WGS

AF:

0.00289

AC:

AN:

3478

EpiCase

AF:

0.0000545

EpiControl

AF:

0.000119

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Jul 21, 2021

- -

not provided

Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 22, 2024

- -

KSR2-related disorder

Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Apr 29, 2019

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

BayesDel_noAF

Benign

-0.53

Cadd

Benign

8.0

Dann

Benign

0.80

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

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