dbSNP rs587777148: KPTN:p.Val244_Leu245insLeuGlnMetTrpSerVal (chr19-47479918-G-GACCGACCACATCTGCAGA) – ACMG Classification: Pathogenic (12 pts)

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:

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 12 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PM4

Nonframeshift variant in NON repetitive region in NM_007059.4.

PP5

Variant 19-47479918-G-GACCGACCACATCTGCAGA is Pathogenic according to our data. Variant chr19-47479918-G-GACCGACCACATCTGCAGA is described in ClinVar as [Likely_pathogenic]. Clinvar id is 100680.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KPTN	NM_007059.4 link	c.714_731dupTCTGCAGATGTGGTCGGT	p.Val244_Leu245insLeuGlnMetTrpSerVal	disruptive_inframe_insertion	Exon 8 of 12	ENST00000338134.8	NP_008990.2	Q9Y664-1A0A384NLB4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KPTN	ENST00000338134.8 link	c.714_731dupTCTGCAGATGTGGTCGGT	p.Val244_Leu245insLeuGlnMetTrpSerVal	disruptive_inframe_insertion	Exon 8 of 12	1	NM_007059.4	ENSP00000337850.2		Q9Y664-1

Frequencies

GnomAD3 genomes

AF:

0.000487

AC:

AN:

151976

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000242

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00113

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000868

Gnomad OTH

AF:

0.000479

GnomAD3 exomes

AF:

0.000488

AC:

121

AN:

247772

Hom.:

AF XY:

0.000460

AC XY:

AN XY:

134730

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000872

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000944

Gnomad NFE exome

AF:

0.000845

Gnomad OTH exome

AF:

0.000499

GnomAD4 exome

AF:

0.000627

AC:

916

AN:

1461292

Hom.:

Cov.:

AF XY:

0.000615

AC XY:

447

AN XY:

726978

show subpopulations

Gnomad4 AFR exome

AF:

0.0000896

Gnomad4 AMR exome

AF:

0.0000671

Gnomad4 ASJ exome

AF:

0.0000383

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00132

Gnomad4 NFE exome

AF:

0.000730

Gnomad4 OTH exome

AF:

0.000431

GnomAD4 genome

AF:

0.000487

AC:

AN:

152094

Hom.:

Cov.:

AF XY:

0.000404

AC XY:

AN XY:

74332

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.0000654

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00113

Gnomad4 NFE

AF:

0.000868

Gnomad4 OTH

AF:

0.000474

Alfa

AF:

0.000474

Hom.:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:13

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Macrocephaly-developmental delay syndrome

Pathogenic:7

Mar 29, 2022

Pittsburgh Clinical Genomics Laboratory, University of Pittsburgh Medical Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence variant is an eighteen nucleotide duplication (dupACCGACCACATCTGCAGA) that results in the inframe insertion of 6 amino acids in exon 8 of 12 of the KPTN gene. This previously reported variant (ClinVar) has been observed in individuals affected by macrocephaly, neurodevelopmental delay and seizures when in the compound heterozygous state (PMID: 32358097). In addition, this variant, when in the compound heterozygous state, co-segregates with this disorder across multiple Ohio Amish families (PMID: 24239382). This variant is rare in control population datasets (gnomAD database, 135 of 279,060 alleles, 0.05%). Routine bioinformatic tools cannot predict the impact this variant will have on the function of kaptin, KPTN's encoded protein. However, protein folding models suggest that this duplication will disrupt the tertiary structure of kaptin (PMID: 24239382), and a functiol study indicates that the protein created by this variant fails to properly localize in neurons (PMID: 24239382). Given this information, we consider this a pathogenic variant. ACMG Criteria: PM3, PM4, PP1, PS3 -

Mar 04, 2025

Institute of Human Genetics, University of Leipzig Medical Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Criteria applied: PM3_VSTR,PS3,PM2,PM4,PP1 -

Sep 03, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant, c.714_731dup, results in the insertion of 6 amino acid(s) of the KPTN protein (p.Met241_Gln246dup), but otherwise preserves the integrity of the reading frame. This variant is present in population databases (rs763764442, gnomAD 0.1%), and has an allele count higher than expected for a pathogenic variant. This variant has been observed in individual(s) with macrocephaly, neurodevelopmental delay and seizures (PMID: 24239382). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 100680). Algorithms developed to predict the effect of variants on gene product structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this variant affects KPTN function (PMID: 24239382). For these reasons, this variant has been classified as Pathogenic. -

Jan 02, 2014

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Aug 25, 2021

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jun 02, 2022

Institute of Human Genetics, Clinical Exome/Genome Diagnostics Group, University Hospital Bonn

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 17, 2023

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with intellectual disability 41 (MIM#615637). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0216 - In-frame insertion in a non-repetitive region that has low conservation. (SP) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD <0.01 for a recessive condition (v2: 135 heterozygotes, 0 homozygotes). (SP) 0604 - Variant is not located in an established domain, motif, hotspot or informative constraint region. (I) 0705 - No comparable in frame duplication variants have previous evidence for pathogenicity. (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. It has been reported in at least six compound heterozygous probands with a neurodevelopmental disorder, including multiple affecteds in a large Amish family. In addition, it has been consistently classified as pathogenic by diagnostic laboratories in ClinVar (PMID:24239382, 32358097). (SP) 1002 - This variant has moderate functional evidence supporting abnormal protein function. In vitro assays have demonstrated protein mislocalization (PMID: 24239382). (SP) 1205 - This variant has been shown to be maternally inherited (by trio analysis). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -

not provided

Pathogenic:4

May 04, 2017

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

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 01, 2021

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 03, 2022

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Published functional studies demonstrate a damaging effect resulting in improper localization of the kaptin protein (Baple et al., 2014); In-frame insertion of 6 amino acids in a non-repeat region; This variant is associated with the following publications: (PMID: 31999056, 24239382, 30008475, 32358097) -

May 21, 2018

Genetic Services Laboratory, University of Chicago

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Inborn genetic diseases

Pathogenic:1

Jul 10, 2023

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.714_731dup18 (p.M241_Q246dup) alteration, located in coding exon 8 of the KPTN gene, results from an in-frame duplication of 18 nucleotides at_x000D_ positions 714 to 731. This results in the duplication of 6 amino acids from codons 241 to 246. Based on data from gnomAD, this allele has an overall frequency of 0.048% (135/279060) total alleles studied. The highest observed frequency was 0.101% (25/24646) of European (Finnish) alleles. This alteration was reported in trans with a second KPTN alteration in multiple individuals with features consistent with KPTN-related neurodevelopmental disorder (Baple, 2014; Thiffault, 2019; Thiffault, 2020). Functional analysis demonstrated that the p.M241_Q246dup alteration led to a mislocalized kaptin protein (Baple, 2014). This alteration is predicted to be deleterious by in silico analysis (Choi, 2012). Based on the available evidence, this alteration is classified as pathogenic. -

KPTN-related disorder

Pathogenic:1

Jul 16, 2024

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The KPTN c.714_731dup18 variant is predicted to result in an in-frame duplication (p.Met241_Gln246dup). This variant has been reported in the compound heterozygous state with a loss of function variant in KPTN (c.776C>A, p.Ser259*) in individuals with global developmental delay, macrocephaly with frontal bossing, high levels of anxiety, and features suggestive of a pervasive developmental disorder (Baple et al. 2014. PubMed ID: 24239382). This variant was also reported along with a splicing variant in KPTN (c.394+1G>A) in an individual with macrocephaly, intractable epilepsy, atrial septal defect, global developmental delay, hypotonia, hypoglycemia, and dysmorphia (Phase not reported, Thiffault et al. 2018. PubMed ID: 30008475). This variant is reported in 0.10% of alleles in individuals of European (Finnish) descent in gnomAD. This variant is interpreted as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

Splicing

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.

rs587777148

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

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