Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. 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. 14/21 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

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:4

Conservation

PhyloP100: 3.54

Publications

3 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 -2 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.13768232).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_007059.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
KPTN	NM_007059.4	MANE Select	c.460G>A	p.Gly154Arg	missense	Exon 5 of 12	NP_008990.2
KPTN	NM_001291296.2		c.292G>A	p.Gly98Arg	missense	Exon 3 of 10	NP_001278225.1
KPTN	NR_111923.2		n.610G>A		non_coding_transcript_exon	Exon 6 of 13

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
KPTN	ENST00000338134.8	TSL:1 MANE Select	c.460G>A	p.Gly154Arg	missense	Exon 5 of 12	ENSP00000337850.2
KPTN	ENST00000595554.1	TSL:3	c.292G>A	p.Gly98Arg	missense	Exon 3 of 8	ENSP00000469446.1
KPTN	ENST00000594139.5	TSL:2	n.228G>A		non_coding_transcript_exon	Exon 4 of 5

Frequencies

GnomAD3 genomes

AF:

0.000131

AC:

AN:

152158

Hom.:

Cov.:

show subpopulations

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

GnomAD2 exomes

AF:

0.0000668

AC:

AN:

194640

AF XY:

0.0000669

show subpopulations

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 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.:

Cov.:

AF XY:

0.0000847

AC XY:

AN XY:

708312

show subpopulations

African (AFR)

AF:

0.0000609

AC:

AN:

32818

American (AMR)

AF:

0.0000762

AC:

AN:

39356

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25550

East Asian (EAS)

AF:

0.00

AC:

AN:

38406

South Asian (SAS)

AF:

0.0000121

AC:

AN:

82700

European-Finnish (FIN)

AF:

0.00

AC:

AN:

51300

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5726

European-Non Finnish (NFE)

AF:

0.000119

AC:

130

AN:

1094704

Other (OTH)

AF:

0.0000169

AC:

AN:

59232

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.459

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome 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

GnomAD4 genome

AF:

0.000131

AC:

AN:

152158

Hom.:

Cov.:

AF XY:

0.000121

AC XY:

AN XY:

74318

show subpopulations

African (AFR)

AF:

0.000145

AC:

AN:

41430

American (AMR)

AF:

0.0000655

AC:

AN:

15266

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5202

South Asian (SAS)

AF:

0.00

AC:

AN:

4834

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10612

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.000191

AC:

AN:

68028

Other (OTH)

AF:

0.00

AC:

AN:

2090

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

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:

0.0000965

Hom.:

Bravo

AF:

0.000140

ESP6500AA

AF:

0.000260

AC:

ESP6500EA

AF:

0.000121

AC:

ExAC

AF:

0.0000333

AC:

ClinVar

ClinVar submissions as Germline

Significance:Uncertain significance

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Inborn genetic diseases (1)

Macrocephaly-developmental delay syndrome (1)

not provided (1)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.21

BayesDel_addAF

Benign

-0.23

BayesDel_noAF

Benign

-0.35

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.080

Eigen

Benign

-0.082

Eigen_PC

Benign

-0.13

FATHMM_MKL

Uncertain

0.81

LIST_S2

Benign

0.85

M_CAP

Benign

0.011

MetaRNN

Benign

0.14

MetaSVM

Benign

-0.92

MutationAssessor

Benign

0.90

PhyloP100

3.5

PrimateAI

Uncertain

0.55

PROVEAN

Benign

-1.5

REVEL

Benign

0.097

Sift

Benign

0.085

Sift4G

Benign

0.086

Polyphen

0.95

Vest4

0.51

MutPred

0.33

Loss of sheet (P = 0.007)

MVP

0.23

MPC

0.62

ClinPred

0.048

GERP RS

5.8

Varity_R

0.12

gMVP

0.38

Mutation Taster

=69/31

polymorphism

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

rs377316863

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

ClinVar submissions as Germline

Computational scores

Splicing

Publications

Other links and lift over