19-47483973-C-G

Position:

• chr19-47483973-C-G

Variant summary

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

The NM_007059.4(KPTN):​c.188G>C​(p.Arg63Pro) variant causes a missense change. The variant allele was found at a frequency of 0.00000274 in 1,461,564 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: KPTN NM_007059.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.22

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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KPTN	NM_007059.4	c.188G>C	p.Arg63Pro	missense_variant	1/12	ENST00000338134.8	NP_008990.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KPTN	ENST00000338134.8	c.188G>C	p.Arg63Pro	missense_variant	1/12	1	NM_007059.4	ENSP00000337850	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000404 AC: 1 AN: 247404 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 134546

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000899

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1461564 Hom.: 0 Cov.: 32 AF XY: 0.00000413 AC XY: 3 AN XY: 727102

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000360

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.23	D
BayesDel_noAF	Uncertain	0.10
CADD	Pathogenic	32
DANN	Uncertain	1.0
DEOGEN2	Benign	0.12	T;T
Eigen	Uncertain	0.65
Eigen_PC	Uncertain	0.62
FATHMM_MKL	Benign	0.56	D
LIST_S2	Uncertain	0.91	D;D
M_CAP	Benign	0.016	T
MetaRNN	Uncertain	0.69	D;D
MetaSVM	Uncertain	-0.23	T
MutationAssessor	Uncertain	2.0	M;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.75	T
PROVEAN	Benign	-2.1	N;.
REVEL	Benign	0.26
Sift	Benign	0.042	D;.
Sift4G	Uncertain	0.014	D;.
Polyphen		0.99	D;.
Vest4		0.79
MutPred		0.62		Loss of MoRF binding (P = 6e-04);Loss of MoRF binding (P = 6e-04);
MVP		0.52
MPC		1.5
ClinPred		0.96	D
GERP RS		4.6
Varity_R		0.75
gMVP		0.92

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: rs142867197; hg19: chr19-47987230;