rs201652303

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_001126049.2(KLLN):c.382C>G(p.Arg128Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00409 in 1,541,338 control chromosomes in the GnomAD database, including 54 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. R128R) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0032 ( 4 hom., cov: 32)

Exomes 𝑓: 0.0042 ( 50 hom. )

Consequence

KLLN
NM_001126049.2 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: 0.563

Publications

8 publications found

Variant links:

Genes affected

KLLN (HGNC:37212): (killin, p53 regulated DNA replication inhibitor) The protein encoded by this intronless gene is found in the nucleus, where it can inhibit DNA synthesis and promote S phase arrest coupled to apoptosis. The expression of this DNA binding protein is upregulated by transcription factor p53. [provided by RefSeq, Dec 2012]

KLLN Gene-Disease associations (from GenCC):

Cowden disease
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
Cowden syndrome 4
Inheritance: Unknown Classification: NO_KNOWN Submitted by: Ambry Genetics

KLLN links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.006397873).

BP6

Variant 10-87862106-G-C is Benign according to our data. Variant chr10-87862106-G-C is described in ClinVar as [Likely_benign]. Clinvar id is 1174734.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.00318 (485/152280) while in subpopulation SAS AF = 0.0191 (92/4828). AF 95% confidence interval is 0.0159. There are 4 homozygotes in GnomAd4. There are 236 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High AC in GnomAd4 at 485 Unknown,AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KLLN	NM_001126049.2 link	c.382C>G	p.Arg128Gly	missense_variant	Exon 1 of 1	ENST00000445946.5	NP_001119521.1	B2CW77

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KLLN	ENST00000445946.5 link	c.382C>G	p.Arg128Gly	missense_variant	Exon 1 of 1	6	NM_001126049.2	ENSP00000392204.2		B2CW77

Frequencies

GnomAD3 genomes

AF:

0.00319

AC:

486

AN:

152162

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000724

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00196

Gnomad ASJ

AF:

0.0225

Gnomad EAS

AF:

0.00483

Gnomad SAS

AF:

0.0192

Gnomad FIN

AF:

0.00132

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.00301

Gnomad OTH

AF:

0.00431

GnomAD2 exomes

AF:

0.00639

AC:

937

AN:

146600

AF XY:

0.00749

show subpopulations

Gnomad AFR exome

AF:

0.000257

Gnomad AMR exome

AF:

0.00215

Gnomad ASJ exome

AF:

0.0190

Gnomad EAS exome

AF:

0.00353

Gnomad FIN exome

AF:

0.00157

Gnomad NFE exome

AF:

0.00380

Gnomad OTH exome

AF:

0.00592

GnomAD4 exome

AF:

0.00418

AC:

5813

AN:

1389058

Hom.:

Cov.:

AF XY:

0.00466

AC XY:

3190

AN XY:

684200

show subpopulations

African (AFR)

AF:

0.000673

AC:

AN:

31220

American (AMR)

AF:

0.00254

AC:

AN:

34608

Ashkenazi Jewish (ASJ)

AF:

0.0194

AC:

470

AN:

24226

East Asian (EAS)

AF:

0.00126

AC:

AN:

35646

South Asian (SAS)

AF:

0.0206

AC:

1614

AN:

78170

European-Finnish (FIN)

AF:

0.00148

AC:

AN:

48724

Middle Eastern (MID)

AF:

0.0194

AC:

109

AN:

5622

European-Non Finnish (NFE)

AF:

0.00284

AC:

3053

AN:

1073308

Other (OTH)

AF:

0.00593

AC:

341

AN:

57534

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.479

Heterozygous variant carriers

331

662

993

1324

1655

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.00318

AC:

485

AN:

152280

Hom.:

Cov.:

AF XY:

0.00317

AC XY:

236

AN XY:

74464

show subpopulations

African (AFR)

AF:

0.000722

AC:

AN:

41570

American (AMR)

AF:

0.00196

AC:

AN:

15298

Ashkenazi Jewish (ASJ)

AF:

0.0225

AC:

AN:

3472

East Asian (EAS)

AF:

0.00484

AC:

AN:

5164

South Asian (SAS)

AF:

0.0191

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00132

AC:

AN:

10616

Middle Eastern (MID)

AF:

0.00680

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00301

AC:

205

AN:

68018

Other (OTH)

AF:

0.00427

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.497

Heterozygous variant carriers

117

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00473

Hom.:

Bravo

AF:

0.00276

ExAC

AF:

0.00968

AC:

226

Asia WGS

AF:

0.00924

AC:

AN:

3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Nov 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

KLLN: BP4, BS1, BS2 -

not specified

Benign:2

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Aug 25, 2020

Genetic Services Laboratory, University of Chicago

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

KLLN-related disorder

Benign:1

May 15, 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

0.23

BayesDel_addAF

Benign

-0.23

BayesDel_noAF

Benign

-0.090

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.056

Eigen

Benign

-0.13

Eigen_PC

Benign

-0.20

FATHMM_MKL

Benign

0.23

MetaRNN

Benign

0.0064

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.0

PhyloP100

0.56

PrimateAI

Benign

0.45

PROVEAN

Pathogenic

-7.0

REVEL

Benign

0.15

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

Polyphen

1.0

Vest4

0.29

MVP

0.36

ClinPred

0.086

GERP RS

2.4

Varity_R

0.55

gMVP

0.019

Mutation Taster

=100/0

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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rs201652303

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over