19-47475482-C-T

Variant names:

• chr19-47475482-C-T
• rs1046273
• NM_007059.4:c.1245G>A

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_007059.4(KPTN):​c.1245G>A​(p.Arg415Arg) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0212 in 1,613,516 control chromosomes in the GnomAD database, including 547 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.018 (46 hom., cov: 31)
  • Exomes 𝑓: 0.022 (501 hom.)
• Consequence: KPTN NM_007059.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.629
• Publications: 5 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

ENSG00000287896 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.45).
• BP6: Variant 19-47475482-C-T is Benign according to our data. Variant chr19-47475482-C-T is described in ClinVar as Benign. ClinVar VariationId is 474856.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.629 with no splicing effect.
• BA1: GnomAdExome4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.0639 is higher than 0.05.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KPTN	NM_007059.4	MANE Select	c.1245G>A	p.Arg415Arg	synonymous	Exon 12 of 12	NP_008990.2
	KPTN	NM_001291296.2		c.1077G>A	p.Arg359Arg	synonymous	Exon 10 of 10	NP_001278225.1
	KPTN	NR_111923.2		n.1391G>A		non_coding_transcript_exon	Exon 13 of 13

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KPTN	ENST00000338134.8	TSL:1 MANE Select	c.1245G>A	p.Arg415Arg	synonymous	Exon 12 of 12	ENSP00000337850.2
	KPTN	ENST00000914957.1		c.1359G>A	p.Arg453Arg	synonymous	Exon 12 of 12	ENSP00000585016.1
	KPTN	ENST00000968682.1		c.1188G>A	p.Arg396Arg	synonymous	Exon 10 of 10	ENSP00000638741.1

Frequencies

GnomAD3 genomes AF: 0.0175 AC: 2667 AN: 152230 Hom.: 44 Cov.: 31

Gnomad AFR AF: 0.00376

Gnomad AMI AF: 0.00877

Gnomad AMR AF: 0.0508

Gnomad ASJ AF: 0.00202

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.0240

Gnomad FIN AF: 0.00781

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0217

Gnomad OTH AF: 0.0196

GnomAD2 exomes AF: 0.0244 AC: 6070 AN: 248588 AF XY: 0.0237

Gnomad AFR exome AF: 0.00318

Gnomad AMR exome AF: 0.0684

Gnomad ASJ exome AF: 0.00279

Gnomad EAS exome AF: 0.0000557

Gnomad FIN exome AF: 0.0129

Gnomad NFE exome AF: 0.0213

Gnomad OTH exome AF: 0.0215

GnomAD4 exome AF: 0.0216 AC: 31554 AN: 1461168 Hom.: 501 Cov.: 31 AF XY: 0.0217 AC XY: 15791 AN XY: 726870

African (AFR) AF: 0.00302 AC: 101 AN: 33470

American (AMR) AF: 0.0659 AC: 2944 AN: 44658

Ashkenazi Jewish (ASJ) AF: 0.00287 AC: 75 AN: 26118

East Asian (EAS) AF: 0.0000756 AC: 3 AN: 39676

South Asian (SAS) AF: 0.0266 AC: 2290 AN: 86182

European-Finnish (FIN) AF: 0.0136 AC: 727 AN: 53392

Middle Eastern (MID) AF: 0.0101 AC: 58 AN: 5764

European-Non Finnish (NFE) AF: 0.0217 AC: 24158 AN: 1111544

Other (OTH) AF: 0.0198 AC: 1198 AN: 60364

GnomAD4 genome AF: 0.0176 AC: 2676 AN: 152348 Hom.: 46 Cov.: 31 AF XY: 0.0181 AC XY: 1352 AN XY: 74498

African (AFR) AF: 0.00375 AC: 156 AN: 41582

American (AMR) AF: 0.0514 AC: 786 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.00202 AC: 7 AN: 3470

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5188

South Asian (SAS) AF: 0.0240 AC: 116 AN: 4830

European-Finnish (FIN) AF: 0.00781 AC: 83 AN: 10630

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

European-Non Finnish (NFE) AF: 0.0217 AC: 1478 AN: 68026

Other (OTH) AF: 0.0194 AC: 41 AN: 2110

Alfa AF: 0.0155 Hom.: 11

Bravo AF: 0.0195

Asia WGS AF: 0.00779 AC: 27 AN: 3478

EpiCase AF: 0.0213

EpiControl AF: 0.0167

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Macrocephaly-developmental delay syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.45
CADD	Benign	7.2
DANN	Benign	0.68
PhyloP100		0.63
Mutation Taster		=100/0	polymorphism (auto)

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: rs1046273; hg19: chr19-47978739; COSMIC: COSV52639435; COSMIC: COSV52639435;