19-47483973-C-T

Variant names:

• chr19-47483973-C-T
• rs142867197
• NM_007059.4:c.188G>A

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

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
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4 B:3
• Conservation: PhyloP100: 4.22

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]

ACMG classification

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 rank	MANE	Protein	UniProt
KPTN	NM_007059.4	c.188G>A	p.Arg63Gln	missense_variant	Exon 1 of 12	ENST00000338134.8	NP_008990.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KPTN	ENST00000338134.8	c.188G>A	p.Arg63Gln	missense_variant	Exon 1 of 12	1	NM_007059.4	ENSP00000337850.2

Frequencies

GnomAD3 genomes AF: 0.00116 AC: 177 AN: 152048 Hom.: 0 Cov.: 32

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.: 1 AF XY: 0.00149 AC XY: 201 AN XY: 134546

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.: 2 Cov.: 32 AF XY: 0.00126 AC XY: 916 AN XY: 727102

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.: 0 Cov.: 32 AF XY: 0.00112 AC XY: 83 AN XY: 74402

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.: 0

Bravo AF: 0.00137

TwinsUK AF: 0.00162 AC: 6

ALSPAC AF: 0.00156 AC: 6

ESP6500AA AF: 0.000258 AC: 1

ESP6500EA AF: 0.00157 AC: 13

ExAC AF: 0.00130 AC: 157

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.00251

EpiControl AF: 0.00243

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:4 Benign:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Uncertain:2

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

- -

May 01, 2017

Genetic Services Laboratory, University of Chicago

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Uncertain:1 Benign:1

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

- -

Mar 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

KPTN: BS2 -

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 v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.59
BayesDel_addAF	Benign	-0.30	T
BayesDel_noAF	Benign	-0.21
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Benign	0.030	T;T
Eigen	Benign	0.12
Eigen_PC	Uncertain	0.24
FATHMM_MKL	Benign	0.51	D
LIST_S2	Uncertain	0.91	D;D
M_CAP	Benign	0.0097	T
MetaRNN	Benign	0.011	T;T
MetaSVM	Benign	-0.77	T
MutationAssessor	Benign	1.4	L;.
PrimateAI	Uncertain	0.65	T
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	T
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

Other links and lift over

dbSNP: rs142867197; hg19: chr19-47987230;