rs1295123083

Variant names:

• chr19-47480341-C-CT
• rs1295123083
• NM_007059.4:c.665dupA

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_007059.4(KPTN):​c.665dupA​(p.Ser223GlufsTer50) variant causes a frameshift change. The variant allele was found at a frequency of 0.00000258 in 1,549,446 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 29)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: KPTN NM_007059.4 frameshift
• Clinical Significance: Pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 5.27
• Publications: 1 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 12 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 19-47480341-C-CT is Pathogenic according to our data. Variant chr19-47480341-C-CT is described in ClinVar as Pathogenic. ClinVar VariationId is 504486.Status of the report is criteria_provided_single_submitter, 1 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.665dupA	p.Ser223GlufsTer50	frameshift	Exon 7 of 12	NP_008990.2	Q9Y664-1
	KPTN	NM_001291296.2		c.497dupA	p.Ser167GlufsTer50	frameshift	Exon 5 of 10	NP_001278225.1
	KPTN	NR_111923.2		n.811dupA		non_coding_transcript_exon	Exon 8 of 13

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KPTN	ENST00000338134.8	TSL:1 MANE Select	c.665dupA	p.Ser223GlufsTer50	frameshift	Exon 7 of 12	ENSP00000337850.2	Q9Y664-1
	KPTN	ENST00000914957.1		c.665dupA	p.Ser223GlufsTer49	frameshift	Exon 7 of 12	ENSP00000585016.1
	KPTN	ENST00000968682.1		c.497dupA	p.Ser167GlufsTer48	frameshift	Exon 5 of 10	ENSP00000638741.1

Frequencies

GnomAD3 genomes AF: 0.00000662 AC: 1 AN: 150952 Hom.: 0 Cov.: 29

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000661

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: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000215 AC: 3 AN: 1398494 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 689756

African (AFR) AF: 0.00 AC: 0 AN: 31590

American (AMR) AF: 0.0000280 AC: 1 AN: 35672

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25138

East Asian (EAS) AF: 0.00 AC: 0 AN: 35722

South Asian (SAS) AF: 0.00 AC: 0 AN: 79210

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 48920

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5688

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1078614

Other (OTH) AF: 0.0000345 AC: 2 AN: 57940

GnomAD4 genome AF: 0.00000662 AC: 1 AN: 150952 Hom.: 0 Cov.: 29 AF XY: 0.00 AC XY: 0 AN XY: 73702

African (AFR) AF: 0.00 AC: 0 AN: 40938

American (AMR) AF: 0.0000661 AC: 1 AN: 15124

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3464

East Asian (EAS) AF: 0.00 AC: 0 AN: 5114

South Asian (SAS) AF: 0.00 AC: 0 AN: 4758

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10486

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67784

Other (OTH) AF: 0.00 AC: 0 AN: 2064

Alfa AF: 0.000132 Hom.: 0

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
2	-	-	Macrocephaly-developmental delay syndrome (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		5.3
Mutation Taster		=71/229	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs1295123083; hg19: chr19-47983598;