rs61743291

chr19-47480979-C-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_007059.4(KPTN):c.504G>A(p.Pro168=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0248 in 1,601,960 control chromosomes in the GnomAD database, including 648 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.021 (74 hom., cov: 31)
  • Exomes 𝑓: 0.025 (574 hom.)
• Consequence: KPTN NM_007059.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -1.74

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 Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.76).
• BP6: Variant 19-47480979-C-T is Benign according to our data. Variant chr19-47480979-C-T is described in ClinVar as [Benign]. Clinvar id is 474857.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.74 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0214 (3257/152246) while in subpopulation NFE AF= 0.0296 (2012/68016). AF 95% confidence interval is 0.0285. There are 74 homozygotes in gnomad4. There are 1694 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 74 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KPTN	NM_007059.4	c.504G>A	p.Pro168=	synonymous_variant	5/12	ENST00000338134.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KPTN	ENST00000338134.8	c.504G>A	p.Pro168=	synonymous_variant	5/12	1	NM_007059.4	P1

Frequencies

GnomAD3 genomes AF: 0.0214 AC: 3260 AN: 152128 Hom.: 74 Cov.: 31

Gnomad AFR AF: 0.00425

Gnomad AMI AF: 0.00658

Gnomad AMR AF: 0.0137

Gnomad ASJ AF: 0.00807

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00477

Gnomad FIN AF: 0.0725

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0296

Gnomad OTH AF: 0.0158

GnomAD3 exomes AF: 0.0218 AC: 4900 AN: 225106 Hom.: 101 AF XY: 0.0211 AC XY: 2585 AN XY: 122268

Gnomad AFR exome AF: 0.00426

Gnomad AMR exome AF: 0.00798

Gnomad ASJ exome AF: 0.00446

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00368

Gnomad FIN exome AF: 0.0752

Gnomad NFE exome AF: 0.0285

Gnomad OTH exome AF: 0.0174

GnomAD4 exome AF: 0.0251 AC: 36401 AN: 1449714 Hom.: 574 Cov.: 32 AF XY: 0.0245 AC XY: 17634 AN XY: 720186

Gnomad4 AFR exome AF: 0.00343

Gnomad4 AMR exome AF: 0.00835

Gnomad4 ASJ exome AF: 0.00548

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00445

Gnomad4 FIN exome AF: 0.0690

Gnomad4 NFE exome AF: 0.0276

Gnomad4 OTH exome AF: 0.0202

GnomAD4 genome AF: 0.0214 AC: 3257 AN: 152246 Hom.: 74 Cov.: 31 AF XY: 0.0228 AC XY: 1694 AN XY: 74438

Gnomad4 AFR AF: 0.00424

Gnomad4 AMR AF: 0.0137

Gnomad4 ASJ AF: 0.00807

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00477

Gnomad4 FIN AF: 0.0725

Gnomad4 NFE AF: 0.0296

Gnomad4 OTH AF: 0.0156

Alfa AF: 0.0243 Hom.: 29

Bravo AF: 0.0160

Asia WGS AF: 0.00289 AC: 10 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Macrocephaly-developmental delay syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 29, 2024

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

May 05, 2021

- -

KPTN-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jul 08, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.76
Cadd	Benign	0.25
Dann	Benign	0.40

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: rs61743291; hg19: chr19-47984236; COSMIC: COSV57646245; COSMIC: COSV57646245;