rs587777148

Variant names:

• chr19-47479918-G-GACCGACCACATCTGCAGA
• rs587777148
• NM_007059.4:c.714_731dupTCTGCAGATGTGGTCGGT

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PM4 PP5_Very_Strong

The NM_007059.4(KPTN):​c.714_731dupTCTGCAGATGTGGTCGGT​(p.Val244_Leu245insLeuGlnMetTrpSerVal) variant causes a disruptive inframe insertion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000614 in 1,613,386 control chromosomes in the GnomAD database, with no homozygous occurrence. It is difficult to determine the true allele frequency of this variant because it is of type INS_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency:
  • Genomes: 𝑓 0.00049 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00063 (0 hom.)
• Consequence: KPTN NM_007059.4 disruptive_inframe_insertion
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:14
• Conservation: PhyloP100: 3.02
• Publications: 3 publications found

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):

• complex neurodevelopmental disorder

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• macrocephaly-developmental delay syndrome

  Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 10 ACMG points.

• PM4: Nonframeshift variant in NON repetitive region in NM_007059.4.
• PP5: Variant 19-47479918-G-GACCGACCACATCTGCAGA is Pathogenic according to our data. Variant chr19-47479918-G-GACCGACCACATCTGCAGA is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 100680.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KPTN	NM_007059.4	MANE Select	c.714_731dupTCTGCAGATGTGGTCGGT	p.Val244_Leu245insLeuGlnMetTrpSerVal	disruptive_inframe_insertion	Exon 8 of 12	NP_008990.2	Q9Y664-1
	KPTN	NM_001291296.2		c.546_563dupTCTGCAGATGTGGTCGGT	p.Val188_Leu189insLeuGlnMetTrpSerVal	disruptive_inframe_insertion	Exon 6 of 10	NP_001278225.1
	KPTN	NR_111923.2		n.860_877dupTCTGCAGATGTGGTCGGT		non_coding_transcript_exon	Exon 9 of 13

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KPTN	ENST00000338134.8	TSL:1 MANE Select	c.714_731dupTCTGCAGATGTGGTCGGT	p.Val244_Leu245insLeuGlnMetTrpSerVal	disruptive_inframe_insertion	Exon 8 of 12	ENSP00000337850.2	Q9Y664-1
	KPTN	ENST00000914957.1		c.714_731dupTCTGCAGATGTGGTCGGT	p.Val244_Leu245insLeuGlnMetTrpSerVal	disruptive_inframe_insertion	Exon 8 of 12	ENSP00000585016.1
	KPTN	ENST00000968682.1		c.546_563dupTCTGCAGATGTGGTCGGT	p.Val188_Leu189insLeuGlnMetTrpSerVal	disruptive_inframe_insertion	Exon 6 of 10	ENSP00000638741.1

Frequencies

GnomAD3 genomes AF: 0.000487 AC: 74 AN: 151976 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.0000242

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: 0.00113

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000868

Gnomad OTH AF: 0.000479

GnomAD2 exomes AF: 0.000488 AC: 121 AN: 247772 AF XY: 0.000460

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000872

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000944

Gnomad NFE exome AF: 0.000845

Gnomad OTH exome AF: 0.000499

GnomAD4 exome AF: 0.000627 AC: 916 AN: 1461292 Hom.: 0 Cov.: 32 AF XY: 0.000615 AC XY: 447 AN XY: 726978

African (AFR) AF: 0.0000896 AC: 3 AN: 33468

American (AMR) AF: 0.0000671 AC: 3 AN: 44686

Ashkenazi Jewish (ASJ) AF: 0.0000383 AC: 1 AN: 26120

East Asian (EAS) AF: 0.00 AC: 0 AN: 39686

South Asian (SAS) AF: 0.00 AC: 0 AN: 86204

European-Finnish (FIN) AF: 0.00132 AC: 70 AN: 53140

Middle Eastern (MID) AF: 0.000173 AC: 1 AN: 5766

European-Non Finnish (NFE) AF: 0.000730 AC: 812 AN: 1111856

Other (OTH) AF: 0.000431 AC: 26 AN: 60366

GnomAD4 genome AF: 0.000487 AC: 74 AN: 152094 Hom.: 0 Cov.: 31 AF XY: 0.000404 AC XY: 30 AN XY: 74332

African (AFR) AF: 0.0000241 AC: 1 AN: 41472

American (AMR) AF: 0.0000654 AC: 1 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5166

South Asian (SAS) AF: 0.00 AC: 0 AN: 4816

European-Finnish (FIN) AF: 0.00113 AC: 12 AN: 10596

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000868 AC: 59 AN: 67976

Other (OTH) AF: 0.000474 AC: 1 AN: 2108

Alfa AF: 0.000474 Hom.: 0

ClinVar

ClinVar submissions as Germline

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
8	-	-	Macrocephaly-developmental delay syndrome (8)
4	-	-	not provided (4)
1	-	-	Inborn genetic diseases (1)
1	-	-	KPTN-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		3.0
Mutation Taster		=67/33	disease causing (ClinVar)

Splicing

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

Other links and lift over

dbSNP: rs587777148; hg19: chr19-47983175;