19-47476545-A-ACGCCCTTCAGGGAGACCACGGCAAGCTCCTGCAGCCCATC

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PVS1_Strong PM2

The NM_007059.4(KPTN):c.1168_1169insGATGGGCTGCAGGAGCTTGCCGTGGTCTCCCTGAAGGGCG(p.Val390GlyfsTer56) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 26)
• Consequence: KPTN NM_007059.4 frameshift
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.54

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]

(HGNC:):

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most 50 bp of the penultimate exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.109 CDS is truncated, and there are 1 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KPTN	NM_007059.4	c.1168_1169insGATGGGCTGCAGGAGCTTGCCGTGGTCTCCCTGAAGGGCG	p.Val390GlyfsTer56	frameshift_variant	11/12	ENST00000338134.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KPTN	ENST00000338134.8	c.1168_1169insGATGGGCTGCAGGAGCTTGCCGTGGTCTCCCTGAAGGGCG	p.Val390GlyfsTer56	frameshift_variant	11/12	1	NM_007059.4	P1
	ENST00000669287.1	n.154_193dup		non_coding_transcript_exon_variant	2/2
KPTN	ENST00000594208.5	c.*802_*803insGATGGGCTGCAGGAGCTTGCCGTGGTCTCCCTGAAGGGCG		3_prime_UTR_variant, NMD_transcript_variant	12/13	2

Frequencies

GnomAD3 genomes Cov.: 26

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 26

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Macrocephaly-developmental delay syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Institute of Human Genetics, University of Leipzig Medical Center

Aug 30, 2022

This variant was identified as homozygous._x000D_ Criteria applied: PVS1_MOD, PM2_SUP -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr19-47979802;