Genetic Variant KSR2:p.Pro919Pro (chr12-117469751-A-G) – ACMG Classification: Benign (-21 pts)

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2

The NM_173598.6(KSR2):c.2757T>C(p.Pro919Pro) 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:4

Conservation

PhyloP100: -0.0200

Publications

3 publications found

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:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -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 VariationId 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 the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High AC in GnomAd4 at 1048 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.2757T>C	p.Pro919Pro	synonymous	Exon 19 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.2757T>C	p.Pro919Pro	synonymous	Exon 19 of 20	ENSP00000339952.4	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

GnomAD2 exomes

AF:

0.00171

AC:

427

AN:

249044

AF XY:

0.00137

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 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

African (AFR)

AF:

0.0254

AC:

850

AN:

33478

American (AMR)

AF:

0.00139

AC:

AN:

44716

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26134

East Asian (EAS)

AF:

0.00

AC:

AN:

39698

South Asian (SAS)

AF:

0.000116

AC:

AN:

86194

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53398

Middle Eastern (MID)

AF:

0.00364

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0000468

AC:

AN:

1111842

Other (OTH)

AF:

0.00219

AC:

132

AN:

60372

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.465

Heterozygous variant carriers

118

178

237

296

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

120

150

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00688

AC:

1048

AN:

152344

Hom.:

Cov.:

AF XY:

0.00655

AC XY:

488

AN XY:

74510

show subpopulations

African (AFR)

AF:

0.0234

AC:

974

AN:

41568

American (AMR)

AF:

0.00392

AC:

AN:

15298

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5190

South Asian (SAS)

AF:

0.000207

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10626

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000735

AC:

AN:

68038

Other (OTH)

AF:

0.00378

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

105

157

210

262

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00631

Hom.:

Bravo

AF:

0.00767

Asia WGS

AF:

0.00289

AC:

AN:

3478

EpiCase

AF:

0.0000545

EpiControl

AF:

0.000119

ClinVar

ClinVar submissions as Germline

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

KSR2-related disorder (1)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.53

CADD

Benign

8.0

(source)

DANN

Benign

0.80

PhyloP100

-0.020

Mutation Taster

=99/1

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over