rs987680167

Variant names:

• chr19-47480291-C-G
• rs987680167
• NM_007059.4:c.709+7G>C

Your query was ambiguous. Multiple possible variants found:

• chr19-47480291-C-G
• chr19-47480291-C-T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_007059.4(KPTN):​c.709+7G>C variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000721 in 1,387,114 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. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 25)
  • Exomes 𝑓: 7.2e-7 (0 hom.)
• Consequence: KPTN NM_007059.4 splice_region, intron
• Scores: Splicing: ADA: 0.00001163
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.00300
• Publications: 0 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):

• macrocephaly-developmental delay syndrome

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

ACMG classification

Our verdict: Likely_benign. The variant received -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.709+7G>C		splice_region_variant, intron_variant	Intron 7 of 11	ENST00000338134.8	NP_008990.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KPTN	ENST00000338134.8	c.709+7G>C		splice_region_variant, intron_variant	Intron 7 of 11	1	NM_007059.4	ENSP00000337850.2
KPTN	ENST00000595554.1	c.541+7G>C		splice_region_variant, intron_variant	Intron 5 of 7	3		ENSP00000469446.1
KPTN	ENST00000600271.5	c.-12+7G>C		splice_region_variant, intron_variant	Intron 8 of 9	5		ENSP00000472291.1
KPTN	ENST00000594208.5	n.*343+7G>C		splice_region_variant, intron_variant	Intron 8 of 12	2		ENSP00000470364.1

Frequencies

GnomAD3 genomes Cov.: 25

GnomAD4 exome AF: 7.21e-7 AC: 1 AN: 1387114 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 684774

African (AFR) AF: 0.00 AC: 0 AN: 31324

American (AMR) AF: 0.00 AC: 0 AN: 35600

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25040

East Asian (EAS) AF: 0.00 AC: 0 AN: 35582

South Asian (SAS) AF: 0.00 AC: 0 AN: 78996

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 48482

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5594

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1069008

Other (OTH) AF: 0.0000174 AC: 1 AN: 57488

GnomAD4 genome Cov.: 25

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Nov 18, 2015

Genetic Services Laboratory, University of Chicago

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	4.3
DANN	Benign	0.54
PhyloP100		0.0030
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000012
dbscSNV1_RF	Benign	0.0
SpliceAI score (max)		0.12		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: rs987680167; hg19: chr19-47983548;