19-47476546-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_007059.4(KPTN):c.1168G>A(p.Val390Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000101 in 1,607,550 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.00011 (0 hom., cov: 26)
  • Exomes 𝑓: 0.00010 (0 hom.)
• Consequence: KPTN NM_007059.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• 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 Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.30085778).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KPTN	NM_007059.4	c.1168G>A	p.Val390Met	missense_variant	11/12	ENST00000338134.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KPTN	ENST00000338134.8	c.1168G>A	p.Val390Met	missense_variant	11/12	1	NM_007059.4	P1
	ENST00000669287.1	n.153C>T		non_coding_transcript_exon_variant	2/2
KPTN	ENST00000594208.5	c.*802G>A		3_prime_UTR_variant, NMD_transcript_variant	12/13	2

Frequencies

GnomAD3 genomes AF: 0.000115 AC: 17 AN: 148264 Hom.: 0 Cov.: 26

Gnomad AFR AF: 0.0000997

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000690

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: 0.000163

Gnomad OTH AF: 0.000506

GnomAD3 exomes AF: 0.000105 AC: 26 AN: 246536 Hom.: 0 AF XY: 0.000104 AC XY: 14 AN XY: 134186

Gnomad AFR exome AF: 0.0000657

Gnomad AMR exome AF: 0.000145

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000983

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000153

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000100 AC: 146 AN: 1459286 Hom.: 0 Cov.: 31 AF XY: 0.0000992 AC XY: 72 AN XY: 725530

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.000157

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000464

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000114

Gnomad4 OTH exome AF: 0.0000830

GnomAD4 genome AF: 0.000115 AC: 17 AN: 148264 Hom.: 0 Cov.: 26 AF XY: 0.0000972 AC XY: 7 AN XY: 72008

Gnomad4 AFR AF: 0.0000997

Gnomad4 AMR AF: 0.0000690

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000163

Gnomad4 OTH AF: 0.000506

Alfa AF: 0.000171 Hom.: 0

Bravo AF: 0.000121

ESP6500AA AF: 0.000487 AC: 2

ESP6500EA AF: 0.000119 AC: 1

ExAC AF: 0.000116 AC: 14

EpiCase AF: 0.0000545

EpiControl AF: 0.000178

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Dec 29, 2017

- -

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 03, 2022

The c.1168G>A (p.V390M) alteration is located in exon 11 (coding exon 11) of the KPTN gene. This alteration results from a G to A substitution at nucleotide position 1168, causing the valine (V) at amino acid position 390 to be replaced by a methionine (M). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

May 01, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.077
BayesDel_addAF	Benign	-0.27	T
BayesDel_noAF	Benign	-0.37
Cadd	Benign	19
Dann	Uncertain	1.0
DEOGEN2	Benign	0.062	T
Eigen	Benign	0.13
Eigen_PC	Benign	0.11
FATHMM_MKL	Uncertain	0.81	D
LIST_S2	Benign	0.86	D
M_CAP	Benign	0.0096	T
MetaRNN	Benign	0.30	T
MetaSVM	Benign	-0.89	T
MutationAssessor	Uncertain	2.4	M
MutationTaster	Benign	0.79	D;D
PrimateAI	Benign	0.42	T
PROVEAN	Benign	-1.5	N
REVEL	Benign	0.054
Sift	Uncertain	0.0060	D
Sift4G	Uncertain	0.032	D
Polyphen		0.97	D
Vest4		0.39
MVP		0.33
MPC		0.45
ClinPred		0.072	T
GERP RS		1.0
Varity_R		0.068
gMVP		0.44

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: rs201244068; hg19: chr19-47979803;