Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2

The NM_007059.4(KPTN):c.504G>A(p.Pro168Pro) 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

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: -1.74

Publications

4 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: Benign. The variant received -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 VariationId 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 the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 74 AR gene

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.504G>A	p.Pro168Pro	synonymous	Exon 5 of 12	NP_008990.2
KPTN	NM_001291296.2		c.336G>A	p.Pro112Pro	synonymous	Exon 3 of 10	NP_001278225.1
KPTN	NR_111923.2		n.654G>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.504G>A	p.Pro168Pro	synonymous	Exon 5 of 12	ENSP00000337850.2
KPTN	ENST00000595554.1	TSL:3	c.336G>A	p.Pro112Pro	synonymous	Exon 3 of 8	ENSP00000469446.1
KPTN	ENST00000594139.5	TSL:2	n.272G>A		non_coding_transcript_exon	Exon 4 of 5

Frequencies

GnomAD3 genomes

AF:

0.0214

AC:

3260

AN:

152128

Hom.:

Cov.:

show subpopulations

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

GnomAD2 exomes

AF:

0.0218

AC:

4900

AN:

225106

AF XY:

0.0211

show subpopulations

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 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.:

AF XY:

0.0245

AC XY:

17634

AN XY:

720186

show subpopulations

African (AFR)

AF:

0.00343

AC:

114

AN:

33242

American (AMR)

AF:

0.00835

AC:

354

AN:

42378

Ashkenazi Jewish (ASJ)

AF:

0.00548

AC:

142

AN:

25914

East Asian (EAS)

AF:

0.00

AC:

AN:

39218

South Asian (SAS)

AF:

0.00445

AC:

378

AN:

85026

European-Finnish (FIN)

AF:

0.0690

AC:

3630

AN:

52614

Middle Eastern (MID)

AF:

0.00382

AC:

AN:

5754

European-Non Finnish (NFE)

AF:

0.0276

AC:

30554

AN:

1105668

Other (OTH)

AF:

0.0202

AC:

1207

AN:

59900

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.465

Heterozygous variant carriers

1708

3416

5124

6832

8540

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1058

2116

3174

4232

5290

<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:

0.0214

AC:

3257

AN:

152246

Hom.:

Cov.:

AF XY:

0.0228

AC XY:

1694

AN XY:

74438

show subpopulations

African (AFR)

AF:

0.00424

AC:

176

AN:

41554

American (AMR)

AF:

0.0137

AC:

209

AN:

15292

Ashkenazi Jewish (ASJ)

AF:

0.00807

AC:

AN:

3470

East Asian (EAS)

AF:

0.000193

AC:

AN:

5184

South Asian (SAS)

AF:

0.00477

AC:

AN:

4818

European-Finnish (FIN)

AF:

0.0725

AC:

768

AN:

10596

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0296

AC:

2012

AN:

68016

Other (OTH)

AF:

0.0156

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

153

306

460

613

766

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

120

160

200

<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:

0.0243

Hom.:

Bravo

AF:

0.0160

Asia WGS

AF:

0.00289

AC:

AN:

3478

ClinVar

ClinVar submissions as Germline

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

KPTN-related disorder (1)

Macrocephaly-developmental delay syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.76

CADD

Benign

0.25

(source)

DANN

Benign

0.40

PhyloP100

-1.7

Mutation Taster

=100/0

polymorphism (auto)

(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

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NM_007059.4:c.504G>A

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