Variant 16-19706962-T-C details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 4P and 2B. PM1PM2BP4_Moderate

The NM_001012991.3(KNOP1):c.1325A>G(p.Lys442Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000131 in 152,326 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)

Consequence

KNOP1
NM_001012991.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.22

Variant links:

Genes affected

KNOP1 (HGNC:34404): (lysine rich nucleolar protein 1) The protein encoded by this gene is a nucleolar protein that interacts with zinc finger 106 protein. The encoded protein has several of the same characteristics as nucleostemin and may be involved in testis development. [provided by RefSeq, Feb 2017]

KNOP1 links:

ENSG00000261312 (HGNC:):

ENSG00000261312 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM1

In a cross_link Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in SUMO2) (size 0) in uniprot entity KNOP1_HUMAN

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.17322493).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KNOP1	NM_001012991.3 linkuse as main transcript	c.1325A>G	p.Lys442Arg	missense_variant	5/5	ENST00000219837.12	NP_001013009.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
KNOP1	ENST00000219837.12 linkuse as main transcript	c.1325A>G	p.Lys442Arg	missense_variant	5/5	1	NM_001012991.3	ENSP00000219837.7	Q1ED39
KNOP1	ENST00000568230.5 linkuse as main transcript	c.362A>G	p.Lys121Arg	missense_variant	4/4	5		ENSP00000455015.1	H3BNU8
ENSG00000261312	ENST00000565916.1 linkuse as main transcript	n.612T>C		non_coding_transcript_exon_variant	1/2	5

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152208

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

Cov.:

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152326

Hom.:

Cov.:

AF XY:

0.0000268

AC XY:

AN XY:

74490

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.0000653

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 17, 2024

The c.1325A>G (p.K442R) alteration is located in exon 5 (coding exon 4) of the KNOP1 gene. This alteration results from a A to G substitution at nucleotide position 1325, causing the lysine (K) at amino acid position 442 to be replaced by an arginine (R). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.088

BayesDel_addAF

Benign

-0.17

BayesDel_noAF

Benign

-0.48

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.086

T;.

Eigen

Benign

0.045

Eigen_PC

Benign

-0.12

FATHMM_MKL

Benign

0.54

LIST_S2

Benign

0.69

T;T

M_CAP

Benign

0.0069

MetaRNN

Benign

0.17

T;T

MetaSVM

Benign

-0.95

MutationAssessor

Uncertain

2.0

M;.

PrimateAI

Benign

0.35

PROVEAN

Benign

-2.2

N;N

REVEL

Benign

0.087

Sift

Benign

0.10

T;T

Sift4G

Benign

0.071

T;D

Polyphen

1.0

D;.

Vest4

0.16

MutPred

0.40

Loss of methylation at K442 (P = 0.0154);.;

MVP

0.40

MPC

0.080

ClinPred

0.43

GERP RS

1.7

Varity_R

0.049

gMVP

0.58

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over