rs766372684

Positions:

• chr19-47480760-C-CTA

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_007059.4(KPTN):​c.598_599insTA​(p.Ser200IlefsTer55) variant causes a frameshift, splice region change. The variant allele was found at a frequency of 0.000122 in 1,613,892 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: 𝑓 0.000092 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00013 (0 hom.)
• Consequence: KPTN NM_007059.4 frameshift, splice_region
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:7
• Conservation: PhyloP100: 6.92

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 Pathogenic. Variant got 18 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 19-47480760-C-CTA is Pathogenic according to our data. Variant chr19-47480760-C-CTA is described in ClinVar as [Likely_pathogenic]. Clinvar id is 279826.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KPTN	NM_007059.4	c.598_599insTA	p.Ser200IlefsTer55	frameshift_variant, splice_region_variant	6/12	ENST00000338134.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KPTN	ENST00000338134.8	c.598_599insTA	p.Ser200IlefsTer55	frameshift_variant, splice_region_variant	6/12	1	NM_007059.4	P1

Frequencies

GnomAD3 genomes AF: 0.0000920 AC: 14 AN: 152132 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.000191

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000112 AC: 28 AN: 249542 Hom.: 0 AF XY: 0.000126 AC XY: 17 AN XY: 135388

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000579

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000928

Gnomad NFE exome AF: 0.000203

Gnomad OTH exome AF: 0.000165

GnomAD4 exome AF: 0.000125 AC: 183 AN: 1461760 Hom.: 0 Cov.: 32 AF XY: 0.000121 AC XY: 88 AN XY: 727174

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.0000447

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.000148

Gnomad4 OTH exome AF: 0.000232

GnomAD4 genome AF: 0.0000920 AC: 14 AN: 152132 Hom.: 0 Cov.: 31 AF XY: 0.0000807 AC XY: 6 AN XY: 74322

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000191

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000978 Hom.: 0

Bravo AF: 0.000102

EpiCase AF: 0.000218

EpiControl AF: 0.0000593

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Macrocephaly-developmental delay syndrome Pathogenic:4

Pathogenic, no assertion criteria provided	literature only	OMIM	Apr 07, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jul 15, 2022	This variant has not been reported in the literature in individuals affected with KPTN-related conditions. For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. ClinVar contains an entry for this variant (Variation ID: 279826). This variant is present in population databases (rs766372684, gnomAD 0.02%). This sequence change creates a premature translational stop signal (p.Ser200Ilefs*55) in the KPTN gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in KPTN are known to be pathogenic (PMID: 24239382, 25847626). -
Pathogenic, criteria provided, single submitter	research	Cavalleri Lab, Royal College of Surgeons in Ireland	Dec 11, 2019	ACMG evidence PVS1, PM3, PP3 -

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Apr 21, 2020	Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 26633542, 31999056, 31980526, 32238909, 32808430) -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2023	KPTN: PVS1, PM2, PM3:Supporting -

Intellectual disability Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

New York Genome Center

Apr 07, 2020

- -

Computational scores

Source: dbNSFP v4.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs766372684; hg19: chr19-47984017;