chr19-47483973-C-T

Position:

chr19-47483973-C-T

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_StrongBP6BS2

The NM_007059.4(KPTN):c.188G>A(p.Arg63Gln) variant causes a missense change. The variant allele was found at a frequency of 0.00121 in 1,613,730 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0012 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0012 ( 2 hom. )

Consequence

KPTN
NM_007059.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4B:3

Conservation

PhyloP100: 4.22

Variant links:

Genes affected

KPTN (HGNC:6404): (kaptin, actin binding protein) This gene encodes a filamentous-actin-associated protein, which is involved in actin dynamics and plays an important role in neuromorphogenesis. This protein is part of the KICSTOR protein complex that localizes to lysosomes. Mutations in this gene result in an autosomal recessive form of intellectual disability. Alternatively spliced transcript variants have been found for this gene. [provided by RefSeq, Jul 2017]

KPTN links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.010958821).

BP6

Variant 19-47483973-C-T is Benign according to our data. Variant chr19-47483973-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 252672.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=4}.

BS2

High Homozygotes in GnomAdExome4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KPTN	NM_007059.4 linkuse as main transcript	c.188G>A	p.Arg63Gln	missense_variant	1/12	ENST00000338134.8	NP_008990.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KPTN	ENST00000338134.8 linkuse as main transcript	c.188G>A	p.Arg63Gln	missense_variant	1/12	1	NM_007059.4	ENSP00000337850	P1	Q9Y664-1

Frequencies

GnomAD3 genomes

AF:

0.00116

AC:

177

AN:

152048

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000217

Gnomad AMI

AF:

0.0110

Gnomad AMR

AF:

0.00301

Gnomad ASJ

AF:

0.00317

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00125

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00949

Gnomad NFE

AF:

0.00131

Gnomad OTH

AF:

0.00144

GnomAD3 exomes

AF:

0.00135

AC:

334

AN:

247404

Hom.:

AF XY:

0.00149

AC XY:

201

AN XY:

134546

show subpopulations

Gnomad AFR exome

AF:

0.0000648

Gnomad AMR exome

AF:

0.00162

Gnomad ASJ exome

AF:

0.00209

Gnomad EAS exome

AF:

0.0000557

Gnomad SAS exome

AF:

0.00144

Gnomad FIN exome

AF:

0.0000930

Gnomad NFE exome

AF:

0.00174

Gnomad OTH exome

AF:

0.00248

GnomAD4 exome

AF:

0.00122

AC:

1778

AN:

1461564

Hom.:

Cov.:

AF XY:

0.00126

AC XY:

916

AN XY:

727102

show subpopulations

Gnomad4 AFR exome

AF:

0.000807

Gnomad4 AMR exome

AF:

0.00172

Gnomad4 ASJ exome

AF:

0.00230

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00125

Gnomad4 FIN exome

AF:

0.000151

Gnomad4 NFE exome

AF:

0.00123

Gnomad4 OTH exome

AF:

0.00134

GnomAD4 genome

AF:

0.00116

AC:

176

AN:

152166

Hom.:

Cov.:

AF XY:

0.00112

AC XY:

AN XY:

74402

show subpopulations

Gnomad4 AFR

AF:

0.000217

Gnomad4 AMR

AF:

0.00301

Gnomad4 ASJ

AF:

0.00317

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00125

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00131

Gnomad4 OTH

AF:

0.00142

Alfa

AF:

0.00153

Hom.:

Bravo

AF:

0.00137

TwinsUK

AF:

0.00162

AC:

ALSPAC

AF:

0.00156

AC:

ESP6500AA

AF:

0.000258

AC:

ESP6500EA

AF:

0.00157

AC:

ExAC

AF:

0.00130

AC:

157

Asia WGS

AF:

0.000866

AC:

AN:

3478

EpiCase

AF:

0.00251

EpiControl

AF:

0.00243

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:4Benign:3

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not specified

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	May 01, 2017	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	Oct 31, 2015	- -

not provided

Uncertain:1Benign:1

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2024	KPTN: BS2 -
Uncertain significance, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	May 19, 2017	- -

Macrocephaly-developmental delay syndrome

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Nov 01, 2022

This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 63 of the KPTN protein (p.Arg63Gln). This variant is present in population databases (rs142867197, gnomAD 0.2%), and has an allele count higher than expected for a pathogenic variant. This variant has not been reported in the literature in individuals affected with KPTN-related conditions. ClinVar contains an entry for this variant (Variation ID: 252672). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt KPTN protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Inborn genetic diseases

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 03, 2022

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

KPTN-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 10, 2022

This variant is classified as likely 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

Pathogenic

0.59

BayesDel_addAF

Benign

-0.30

BayesDel_noAF

Benign

-0.21

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Benign

0.030

T;T

Eigen

Benign

0.12

Eigen_PC

Uncertain

0.24

FATHMM_MKL

Benign

0.51

LIST_S2

Uncertain

0.91

D;D

M_CAP

Benign

0.0097

MetaRNN

Benign

0.011

T;T

MetaSVM

Benign

-0.77

MutationAssessor

Benign

1.4

L;.

MutationTaster

Benign

1.0

D;D

PrimateAI

Uncertain

0.65

PROVEAN

Benign

-0.40

N;.

REVEL

Benign

0.19

Sift

Benign

0.19

T;.

Sift4G

Benign

0.18

T;.

Polyphen

0.28

B;.

Vest4

0.54

MVP

0.35

MPC

0.86

ClinPred

0.063

GERP RS

4.6

Varity_R

0.26

gMVP

0.66

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