10-87862096-T-C

Position:

• chr10-87862096-T-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.392A>G​(p.Asn131Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00456 in 1,535,210 control chromosomes in the GnomAD database, including 63 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/18 in silico tools predict 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: 0.0045 (57 hom.)
• Consequence: KLLN NM_001126049.2 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.171

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=0.0028946996).
• BP6: Variant 10-87862096-T-C is Benign according to our data. Variant chr10-87862096-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 1337856.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-87862096-T-C is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00503 (765/152206) while in subpopulation SAS AF= 0.0195 (94/4820). AF 95% confidence interval is 0.0163. There are 6 homozygotes in gnomad4. There are 370 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 765 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KLLN	NM_001126049.2	c.392A>G	p.Asn131Ser	missense_variant	1/1	ENST00000445946.5	NP_001119521.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KLLN	ENST00000445946.5	c.392A>G	p.Asn131Ser	missense_variant	1/1		NM_001126049.2	ENSP00000392204	P1

Frequencies

GnomAD3 genomes AF: 0.00500 AC: 761 AN: 152088 Hom.: 5 Cov.: 32

Gnomad AFR AF: 0.00538

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00602

Gnomad ASJ AF: 0.0237

Gnomad EAS AF: 0.00483

Gnomad SAS AF: 0.0197

Gnomad FIN AF: 0.00132

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.00322

Gnomad OTH AF: 0.00432

GnomAD3 exomes AF: 0.00693 AC: 976 AN: 140928 Hom.: 5 AF XY: 0.00783 AC XY: 583 AN XY: 74432

Gnomad AFR exome AF: 0.00566

Gnomad AMR exome AF: 0.00366

Gnomad ASJ exome AF: 0.0211

Gnomad EAS exome AF: 0.00350

Gnomad SAS exome AF: 0.0202

Gnomad FIN exome AF: 0.00161

Gnomad NFE exome AF: 0.00383

Gnomad OTH exome AF: 0.00561

GnomAD4 exome AF: 0.00450 AC: 6228 AN: 1383004 Hom.: 57 Cov.: 31 AF XY: 0.00493 AC XY: 3356 AN XY: 680808

Gnomad4 AFR exome AF: 0.00602

Gnomad4 AMR exome AF: 0.00375

Gnomad4 ASJ exome AF: 0.0221

Gnomad4 EAS exome AF: 0.00126

Gnomad4 SAS exome AF: 0.0207

Gnomad4 FIN exome AF: 0.00149

Gnomad4 NFE exome AF: 0.00295

Gnomad4 OTH exome AF: 0.00704

GnomAD4 genome AF: 0.00503 AC: 765 AN: 152206 Hom.: 6 Cov.: 32 AF XY: 0.00497 AC XY: 370 AN XY: 74426

Gnomad4 AFR AF: 0.00549

Gnomad4 AMR AF: 0.00601

Gnomad4 ASJ AF: 0.0237

Gnomad4 EAS AF: 0.00484

Gnomad4 SAS AF: 0.0195

Gnomad4 FIN AF: 0.00132

Gnomad4 NFE AF: 0.00322

Gnomad4 OTH AF: 0.00427

Alfa AF: 0.00460 Hom.: 3

Bravo AF: 0.00462

ESP6500AA AF: 0.00506 AC: 7

ESP6500EA AF: 0.00220 AC: 7

ExAC AF: 0.0103 AC: 249

Asia WGS AF: 0.0120 AC: 41 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Aug 25, 2020

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.030
BayesDel_addAF	Benign	-0.56	T
BayesDel_noAF	Benign	-0.56
CADD	Benign	12
DANN	Benign	0.78
DEOGEN2	Benign	0.00093	T
Eigen	Benign	-0.80
Eigen_PC	Benign	-0.68
FATHMM_MKL	Benign	0.0023	N
MetaRNN	Benign	0.0029	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.0	N
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.44	T
PROVEAN	Benign	2.7	N
REVEL	Benign	0.028
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.052
ClinPred		0.016	T
GERP RS		1.3
Varity_R		0.039
gMVP		0.0017

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: rs147932146; hg19: chr10-89621853;