10-87862106-G-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

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. 12/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as 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
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.563

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]

ACMG classification

Verdict is Benign. Variant got -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 [Benign]. Clinvar id is 1174734.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-87862106-G-C is described in Lovd as [Benign]. Variant chr10-87862106-G-C is described in Lovd as [Likely_benign].
• 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 male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd at 486 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KLLN	NM_001126049.2	c.382C>G	p.Arg128Gly	missense_variant	1/1	ENST00000445946.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KLLN	ENST00000445946.5	c.382C>G	p.Arg128Gly	missense_variant	1/1		NM_001126049.2	P1

Frequencies

GnomAD3 genomes AF: 0.00319 AC: 486 AN: 152162 Hom.: 4 Cov.: 32

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

GnomAD3 exomes AF: 0.00639 AC: 937 AN: 146600 Hom.: 6 AF XY: 0.00749 AC XY: 582 AN XY: 77678

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 SAS exome AF: 0.0204

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.: 50 Cov.: 31 AF XY: 0.00466 AC XY: 3190 AN XY: 684200

Gnomad4 AFR exome AF: 0.000673

Gnomad4 AMR exome AF: 0.00254

Gnomad4 ASJ exome AF: 0.0194

Gnomad4 EAS exome AF: 0.00126

Gnomad4 SAS exome AF: 0.0206

Gnomad4 FIN exome AF: 0.00148

Gnomad4 NFE exome AF: 0.00284

Gnomad4 OTH exome AF: 0.00593

GnomAD4 genome AF: 0.00318 AC: 485 AN: 152280 Hom.: 4 Cov.: 32 AF XY: 0.00317 AC XY: 236 AN XY: 74464

Gnomad4 AFR AF: 0.000722

Gnomad4 AMR AF: 0.00196

Gnomad4 ASJ AF: 0.0225

Gnomad4 EAS AF: 0.00484

Gnomad4 SAS AF: 0.0191

Gnomad4 FIN AF: 0.00132

Gnomad4 NFE AF: 0.00301

Gnomad4 OTH AF: 0.00427

Alfa AF: 0.00473 Hom.: 1

Bravo AF: 0.00276

ExAC AF: 0.00968 AC: 226

Asia WGS AF: 0.00924 AC: 32 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Aug 25, 2020	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2023	KLLN: BP4, BS1, BS2 -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -

KLLN-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

May 15, 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
AlphaMissense	Benign	0.23
BayesDel_addAF	Benign	-0.23	T
BayesDel_noAF	Benign	-0.090
Cadd	Benign	19
Dann	Uncertain	0.99
DEOGEN2	Benign	0.056	T
Eigen	Benign	-0.13
Eigen_PC	Benign	-0.20
FATHMM_MKL	Benign	0.23	N
MetaRNN	Benign	0.0064	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.0	N
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.45	T
PROVEAN	Pathogenic	-7.0	D
REVEL	Benign	0.15
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.29
MVP		0.36
ClinPred		0.086	T
GERP RS		2.4
Varity_R		0.55
gMVP		0.019

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

Other links and lift over

dbSNP: rs201652303; hg19: chr10-89621863;