NM_001126049.2:c.445T>A

Variant names:

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_StrongBS1BS2

The NM_001126049.2(KLLN):c.445T>A(p.Trp149Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00446 in 1,490,586 control chromosomes in the GnomAD database, including 63 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0050 ( 6 hom., cov: 32)

Exomes 𝑓: 0.0044 ( 57 hom. )

Consequence

KLLN
NM_001126049.2 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: 0.290

Publications

9 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 -16 ACMG points.

BP6

Variant 10-87862043-A-T is Benign according to our data. Variant chr10-87862043-A-T is described in ClinVar as [Likely_benign]. Clinvar id is 1337818.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 = 0.00504 (767/152320) while in subpopulation SAS AF = 0.0197 (95/4832). AF 95% confidence interval is 0.0165. There are 6 homozygotes in GnomAd4. There are 372 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High AC in GnomAd4 at 767 Unknown,AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KLLN	NM_001126049.2 link	c.445T>A	p.Trp149Arg	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.445T>A	p.Trp149Arg	missense_variant	Exon 1 of 1	6	NM_001126049.2	ENSP00000392204.2		B2CW77

Frequencies

GnomAD3 genomes

AF:

0.00501

AC:

763

AN:

152202

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00538

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00602

Gnomad ASJ

AF:

0.0236

Gnomad EAS

AF:

0.00483

Gnomad SAS

AF:

0.0199

Gnomad FIN

AF:

0.00132

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.00323

Gnomad OTH

AF:

0.00431

GnomAD2 exomes

AF:

0.00654

AC:

675

AN:

103242

AF XY:

0.00719

show subpopulations

Gnomad AFR exome

AF:

0.00537

Gnomad AMR exome

AF:

0.00444

Gnomad ASJ exome

AF:

0.0215

Gnomad EAS exome

AF:

0.00351

Gnomad FIN exome

AF:

0.00169

Gnomad NFE exome

AF:

0.00376

Gnomad OTH exome

AF:

0.00640

GnomAD4 exome

AF:

0.00440

AC:

5887

AN:

1338266

Hom.:

Cov.:

AF XY:

0.00478

AC XY:

3128

AN XY:

654270

show subpopulations

African (AFR)

AF:

0.00594

AC:

175

AN:

29456

American (AMR)

AF:

0.00418

AC:

109

AN:

26088

Ashkenazi Jewish (ASJ)

AF:

0.0224

AC:

460

AN:

20540

East Asian (EAS)

AF:

0.00128

AC:

AN:

35292

South Asian (SAS)

AF:

0.0209

AC:

1458

AN:

69756

European-Finnish (FIN)

AF:

0.00150

AC:

AN:

46666

Middle Eastern (MID)

AF:

0.0220

AC:

118

AN:

5362

European-Non Finnish (NFE)

AF:

0.00293

AC:

3073

AN:

1049988

Other (OTH)

AF:

0.00688

AC:

379

AN:

55118

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.476

Heterozygous variant carriers

339

677

1016

1354

1693

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.00504

AC:

767

AN:

152320

Hom.:

Cov.:

AF XY:

0.00499

AC XY:

372

AN XY:

74488

show subpopulations

African (AFR)

AF:

0.00548

AC:

228

AN:

41574

American (AMR)

AF:

0.00601

AC:

AN:

15312

Ashkenazi Jewish (ASJ)

AF:

0.0236

AC:

AN:

3470

East Asian (EAS)

AF:

0.00484

AC:

AN:

5164

South Asian (SAS)

AF:

0.0197

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.00132

AC:

AN:

10626

Middle Eastern (MID)

AF:

0.00680

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00323

AC:

220

AN:

68024

Other (OTH)

AF:

0.00426

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

111

148

185

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00460

Hom.:

Bravo

AF:

0.00461

TwinsUK

AF:

0.00297

AC:

ALSPAC

AF:

0.00285

AC:

ESP6500AA

AF:

0.00578

AC:

ESP6500EA

AF:

0.00220

AC:

ExAC

AF:

0.00617

AC:

164

Asia WGS

AF:

0.0120

AC:

AN:

3478

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

Nov 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

KLLN: BS1, BS2 -

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

not specified

Benign:1

Aug 25, 2020

Genetic Services Laboratory, University of Chicago

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.62

BayesDel_addAF

Benign

-0.32

BayesDel_noAF

Benign

-0.22

CADD

Benign

(source)

DANN

Benign

0.66

DEOGEN2

Benign

0.073

Eigen

Benign

-1.2

Eigen_PC

Benign

-1.2

FATHMM_MKL

Benign

0.079

MetaRNN

Benign

0.0049

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.0

PhyloP100

0.29

PrimateAI

Uncertain

0.52

PROVEAN

Pathogenic

-13

REVEL

Benign

0.081

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

Polyphen

0.053

Vest4

0.52

MutPred

0.27

Gain of disorder (P = 0.0032);

MVP

0.19

ClinPred

0.065

GERP RS

0.22

Varity_R

0.45

gMVP

0.020

Mutation Taster

=99/1

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.32

Details are displayed if max score is > 0.2

DS_AG_spliceai

0.32

Position offset: -2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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NM_001126049.2:c.445T>A

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