rs73940855

Positions:

• chr19-47476658-G-A

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.1056C>T​(p.His352His) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00286 in 1,612,904 control chromosomes in the GnomAD database, including 85 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.014 (43 hom., cov: 27)
  • Exomes 𝑓: 0.0017 (42 hom.)
• Consequence: KPTN NM_007059.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -2.17

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]

ENSG00000287896 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BP6: Variant 19-47476658-G-A is Benign according to our data. Variant chr19-47476658-G-A is described in ClinVar as [Benign]. Clinvar id is 474855.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-2.17 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0141 (2134/151576) while in subpopulation AFR AF= 0.0485 (2005/41340). AF 95% confidence interval is 0.0467. There are 43 homozygotes in gnomad4. There are 1015 alleles in male gnomad4 subpopulation. Median coverage is 27. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 43 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KPTN	NM_007059.4	c.1056C>T	p.His352His	synonymous_variant	11/12	ENST00000338134.8	NP_008990.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KPTN	ENST00000338134.8	c.1056C>T	p.His352His	synonymous_variant	11/12	1	NM_007059.4	ENSP00000337850.2
KPTN	ENST00000594208.5	n.*690C>T		non_coding_transcript_exon_variant	12/13	2		ENSP00000470364.1
ENSG00000287896	ENST00000669287.1	n.265G>A		non_coding_transcript_exon_variant	2/2
KPTN	ENST00000594208.5	n.*690C>T		3_prime_UTR_variant	12/13	2		ENSP00000470364.1

Frequencies

GnomAD3 genomes AF: 0.0140 AC: 2122 AN: 151456 Hom.: 42 Cov.: 27

Gnomad AFR AF: 0.0484

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00548

Gnomad ASJ AF: 0.00231

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000209

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000280

Gnomad OTH AF: 0.00867

GnomAD3 exomes AF: 0.00338 AC: 833 AN: 246242 Hom.: 15 AF XY: 0.00259 AC XY: 348 AN XY: 134168

Gnomad AFR exome AF: 0.0463

Gnomad AMR exome AF: 0.00204

Gnomad ASJ exome AF: 0.00221

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000230

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000314

Gnomad OTH exome AF: 0.00100

GnomAD4 exome AF: 0.00170 AC: 2480 AN: 1461328 Hom.: 42 Cov.: 31 AF XY: 0.00150 AC XY: 1087 AN XY: 726926

Gnomad4 AFR exome AF: 0.0498

Gnomad4 AMR exome AF: 0.00260

Gnomad4 ASJ exome AF: 0.00310

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000197

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000299

Gnomad4 OTH exome AF: 0.00411

GnomAD4 genome AF: 0.0141 AC: 2134 AN: 151576 Hom.: 43 Cov.: 27 AF XY: 0.0137 AC XY: 1015 AN XY: 74038

Gnomad4 AFR AF: 0.0485

Gnomad4 AMR AF: 0.00547

Gnomad4 ASJ AF: 0.00231

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000209

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000280

Gnomad4 OTH AF: 0.00857

Alfa AF: 0.00723 Hom.: 13

Bravo AF: 0.0163

Asia WGS AF: 0.00260 AC: 9 AN: 3478

EpiCase AF: 0.000491

EpiControl AF: 0.000595

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

Labcorp Genetics (formerly Invitae), Labcorp

Jan 13, 2024

- -

not provided Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

KPTN-related disorder Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

May 15, 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	-0.89
CADD	Benign	0.072
DANN	Benign	0.72

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: rs73940855; hg19: chr19-47979915;