rs377316863

chr19-47481023-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_007059.4(KPTN):c.460G>A(p.Gly154Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000992 in 1,581,950 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 0.00013 (0 hom., cov: 31)
  • Exomes 𝑓: 0.000096 (0 hom.)
• Consequence: KPTN NM_007059.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:4
• Conservation: PhyloP100: 3.54

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.13768232).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KPTN	NM_007059.4	c.460G>A	p.Gly154Arg	missense_variant	5/12	ENST00000338134.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KPTN	ENST00000338134.8	c.460G>A	p.Gly154Arg	missense_variant	5/12	1	NM_007059.4	P1

Frequencies

GnomAD3 genomes AF: 0.000131 AC: 20 AN: 152158 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.000145

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: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000191

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000668 AC: 13 AN: 194640 Hom.: 0 AF XY: 0.0000669 AC XY: 7 AN XY: 104614

Gnomad AFR exome AF: 0.0000902

Gnomad AMR exome AF: 0.0000710

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000383

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000108

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000958 AC: 137 AN: 1429792 Hom.: 0 Cov.: 32 AF XY: 0.0000847 AC XY: 60 AN XY: 708312

Gnomad4 AFR exome AF: 0.0000609

Gnomad4 AMR exome AF: 0.0000762

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000121

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000119

Gnomad4 OTH exome AF: 0.0000169

GnomAD4 genome AF: 0.000131 AC: 20 AN: 152158 Hom.: 0 Cov.: 31 AF XY: 0.000121 AC XY: 9 AN XY: 74318

Gnomad4 AFR AF: 0.000145

Gnomad4 AMR AF: 0.0000655

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: 0.0000965 Hom.: 0

Bravo AF: 0.000140

ESP6500AA AF: 0.000260 AC: 1

ESP6500EA AF: 0.000121 AC: 1

ExAC AF: 0.0000333 AC: 4

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:4

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

Apr 13, 2017

- -

Macrocephaly-developmental delay syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Dec 06, 2022

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. 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. ClinVar contains an entry for this variant (Variation ID: 435680). This variant has not been reported in the literature in individuals affected with KPTN-related conditions. This variant is present in population databases (rs377316863, gnomAD 0.02%). This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 154 of the KPTN protein (p.Gly154Arg). -

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 04, 2022

The c.460G>A (p.G154R) alteration is located in exon 5 (coding exon 5) of the KPTN gene. This alteration results from a G to A substitution at nucleotide position 460, causing the glycine (G) at amino acid position 154 to be replaced by an arginine (R). 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

Mayo Clinic Laboratories, Mayo Clinic

Mar 03, 2017

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.21
BayesDel_addAF	Benign	-0.23	T
BayesDel_noAF	Benign	-0.35
Cadd	Benign	23
Dann	Uncertain	0.99
DEOGEN2	Benign	0.080	T;T
Eigen	Benign	-0.082
Eigen_PC	Benign	-0.13
FATHMM_MKL	Uncertain	0.81	D
LIST_S2	Benign	0.85	T;D
M_CAP	Benign	0.011	T
MetaRNN	Benign	0.14	T;T
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	0.90	L;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.55	T
PROVEAN	Benign	-1.5	N;.
REVEL	Benign	0.097
Sift	Benign	0.085	T;.
Sift4G	Benign	0.086	T;.
Polyphen		0.95	P;.
Vest4		0.51
MutPred		0.33		Loss of sheet (P = 0.007);.;
MVP		0.23
MPC		0.62
ClinPred		0.048	T
GERP RS		5.8
Varity_R		0.12
gMVP		0.38

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: rs377316863; hg19: chr19-47984280;