rs200513352

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4_StrongBP6

The NM_007059.4(KPTN):c.761T>C(p.Ile254Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000425 in 1,613,504 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00090 ( 1 hom., cov: 31)

Exomes 𝑓: 0.00037 ( 1 hom. )

Consequence

KPTN
NM_007059.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:2

Conservation

PhyloP100: 2.54

Publications

2 publications found

Variant links:

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]

KPTN Gene-Disease associations (from GenCC):

macrocephaly-developmental delay syndrome
Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet

KPTN links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -5 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.012604177).

BP6

Variant 19-47479889-A-G is Benign according to our data. Variant chr19-47479889-A-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 435676.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KPTN	NM_007059.4 link	c.761T>C	p.Ile254Thr	missense_variant	Exon 8 of 12	ENST00000338134.8	NP_008990.2	Q9Y664-1A0A384NLB4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KPTN	ENST00000338134.8 link	c.761T>C	p.Ile254Thr	missense_variant	Exon 8 of 12	1	NM_007059.4	ENSP00000337850.2		Q9Y664-1

Frequencies

GnomAD3 genomes

AF:

0.000902

AC:

137

AN:

151946

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000871

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00432

Gnomad ASJ

AF:

0.000865

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000383

Gnomad OTH

AF:

0.00239

GnomAD2 exomes

AF:

0.000599

AC:

149

AN:

248580

AF XY:

0.000600

show subpopulations

Gnomad AFR exome

AF:

0.000715

Gnomad AMR exome

AF:

0.00212

Gnomad ASJ exome

AF:

0.00110

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000426

Gnomad OTH exome

AF:

0.000994

GnomAD4 exome

AF:

0.000375

AC:

548

AN:

1461440

Hom.:

Cov.:

AF XY:

0.000370

AC XY:

269

AN XY:

727070

show subpopulations

African (AFR)

AF:

0.000508

AC:

AN:

33472

American (AMR)

AF:

0.00221

AC:

AN:

44698

Ashkenazi Jewish (ASJ)

AF:

0.00184

AC:

AN:

26124

East Asian (EAS)

AF:

0.00

AC:

AN:

39698

South Asian (SAS)

AF:

0.00

AC:

AN:

86218

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53300

Middle Eastern (MID)

AF:

0.000867

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.000306

AC:

340

AN:

1111790

Other (OTH)

AF:

0.000646

AC:

AN:

60374

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.464

Heterozygous variant carriers

103

129

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000901

AC:

137

AN:

152064

Hom.:

Cov.:

AF XY:

0.000955

AC XY:

AN XY:

74342

show subpopulations

African (AFR)

AF:

0.000869

AC:

AN:

41446

American (AMR)

AF:

0.00431

AC:

AN:

15300

Ashkenazi Jewish (ASJ)

AF:

0.000865

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5162

South Asian (SAS)

AF:

0.000208

AC:

AN:

4818

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10608

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000383

AC:

AN:

67944

Other (OTH)

AF:

0.00237

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.511

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000516

Hom.:

Bravo

AF:

0.000956

ESP6500AA

AF:

0.00100

AC:

ESP6500EA

AF:

0.000483

AC:

ExAC

AF:

0.000339

AC:

EpiCase

AF:

0.000600

EpiControl

AF:

0.000356

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Feb 22, 2016

Genetic Services Laboratory, University of Chicago

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Macrocephaly-developmental delay syndrome

Benign:1

Nov 06, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Inborn genetic diseases

Benign:1

Sep 12, 2022

Ambry Genetics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.095

BayesDel_addAF

Benign

-0.45

BayesDel_noAF

Benign

-0.41

CADD

Benign

(source)

DANN

Benign

0.92

DEOGEN2

Benign

0.023

T;T;T

Eigen

Benign

-0.45

Eigen_PC

Benign

-0.25

FATHMM_MKL

Uncertain

0.77

LIST_S2

Benign

0.78

T;T;T

M_CAP

Benign

0.0077

MetaRNN

Benign

0.013

T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.9

L;.;.

PhyloP100

2.5

PrimateAI

Uncertain

0.62

PROVEAN

Benign

0.070

N;.;.

REVEL

Benign

0.076

Sift

Benign

0.85

T;.;.

Sift4G

Benign

0.78

T;.;.

Polyphen

0.0

B;.;.

Vest4

0.33

MVP

0.38

MPC

0.49

ClinPred

0.010

GERP RS

4.2

Varity_R

0.050

gMVP

0.37

Mutation Taster

=83/17

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over