19-47483973-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -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

Publications

3 publications found

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 Gene-Disease associations (from GenCC):

macrocephaly-developmental delay syndrome
Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet

KPTN links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -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 VariationId is 252672.

BS2

High Homozygotes in GnomAdExome4 at 2 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_007059.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
KPTN	NM_007059.4	MANE Select	c.188G>A	p.Arg63Gln	missense	Exon 1 of 12	NP_008990.2
KPTN	NM_001291296.2		c.188G>A	p.Arg63Gln	missense	Exon 1 of 10	NP_001278225.1
KPTN	NR_111923.2		n.247G>A		non_coding_transcript_exon	Exon 1 of 13

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
KPTN	ENST00000338134.8	TSL:1 MANE Select	c.188G>A	p.Arg63Gln	missense	Exon 1 of 12	ENSP00000337850.2
KPTN	ENST00000595554.1	TSL:3	c.188G>A	p.Arg63Gln	missense	Exon 1 of 8	ENSP00000469446.1
KPTN	ENST00000594208.5	TSL:2	n.188G>A		non_coding_transcript_exon	Exon 1 of 13	ENSP00000470364.1

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

GnomAD2 exomes

AF:

0.00135

AC:

334

AN:

247404

AF XY:

0.00149

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 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

African (AFR)

AF:

0.000807

AC:

AN:

33478

American (AMR)

AF:

0.00172

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00230

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00125

AC:

108

AN:

86256

European-Finnish (FIN)

AF:

0.000151

AC:

AN:

53098

Middle Eastern (MID)

AF:

0.00936

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00123

AC:

1363

AN:

1112010

Other (OTH)

AF:

0.00134

AC:

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.464

Heterozygous variant carriers

194

291

388

485

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

104

156

208

260

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00116

AC:

176

AN:

152166

Hom.:

Cov.:

AF XY:

0.00112

AC XY:

AN XY:

74402

show subpopulations

African (AFR)

AF:

0.000217

AC:

AN:

41504

American (AMR)

AF:

0.00301

AC:

AN:

15306

Ashkenazi Jewish (ASJ)

AF:

0.00317

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5172

South Asian (SAS)

AF:

0.00125

AC:

AN:

4812

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10610

Middle Eastern (MID)

AF:

0.00680

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00131

AC:

AN:

67976

Other (OTH)

AF:

0.00142

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.481

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00142

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

May 01, 2017

Genetic Services Laboratory, University of Chicago

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Oct 31, 2015

Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

not provided

Uncertain:1Benign:1

May 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

KPTN: BS2

May 19, 2017

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Macrocephaly-developmental delay syndrome

Uncertain:1

Nov 01, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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

Jun 03, 2022

Ambry Genetics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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

Feb 10, 2022

PreventionGenetics, part of Exact Sciences

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

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 v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.59

BayesDel_addAF

Benign

-0.30

BayesDel_noAF

Benign

-0.21

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.030

Eigen

Benign

0.12

Eigen_PC

Uncertain

0.24

FATHMM_MKL

Benign

0.51

LIST_S2

Uncertain

0.91

M_CAP

Benign

0.0097

MetaRNN

Benign

0.011

MetaSVM

Benign

-0.77

MutationAssessor

Benign

1.4

PhyloP100

4.2

PrimateAI

Uncertain

0.65

PROVEAN

Benign

-0.40

REVEL

Benign

0.19

Sift

Benign

0.19

Sift4G

Benign

0.18

Polyphen

0.28

Vest4

0.54

MVP

0.35

MPC

0.86

ClinPred

0.063

GERP RS

4.6

PromoterAI

-0.12

Neutral

(source)

Varity_R

0.26

gMVP

0.66

Mutation Taster

=277/23

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over