19-47476719-G-C

Variant names:

• chr19-47476719-G-C
• rs1046029135
• NM_007059.4:c.1000-5C>G

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_007059.4(KPTN):​c.1000-5C>G variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,457,942 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 27)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: KPTN NM_007059.4 splice_region, intron
• Scores: Splicing: ADA: 0.001454
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.11

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]

ENSG00000287896 (HGNC:):

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KPTN	NM_007059.4	c.1000-5C>G		splice_region_variant, intron_variant	Intron 10 of 11	ENST00000338134.8	NP_008990.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KPTN	ENST00000338134.8	c.1000-5C>G		splice_region_variant, intron_variant	Intron 10 of 11	1	NM_007059.4	ENSP00000337850.2
ENSG00000287896	ENST00000669287.1	n.326G>C		non_coding_transcript_exon_variant	Exon 2 of 2
KPTN	ENST00000594208.5	n.*634-5C>G		splice_region_variant, intron_variant	Intron 11 of 12	2		ENSP00000470364.1
KPTN	ENST00000595554.1	c.*125C>G		downstream_gene_variant		3		ENSP00000469446.1

Frequencies

GnomAD3 genomes Cov.: 27

GnomAD3 exomes AF: 0.00000416 AC: 1 AN: 240374 Hom.: 0 AF XY: 0.00000765 AC XY: 1 AN XY: 130692

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000919

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1457942 Hom.: 0 Cov.: 31 AF XY: 0.00000276 AC XY: 2 AN XY: 724752

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000253

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.01e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 27

Alfa AF: 0.0000225 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	0.15
DANN	Benign	0.74

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0015
dbscSNV1_RF	Benign	0.070
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs1046029135; hg19: chr19-47979976;