rs73940855

Variant names:

• chr19-47476658-G-A
• rs73940855
• NM_007059.4:c.1056C>T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_007059.4(KPTN):​c.1056C>T​(p.His352His) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00286 in 1,612,904 control chromosomes in the GnomAD database, including 85 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.014 (43 hom., cov: 27)
  • Exomes 𝑓: 0.0017 (42 hom.)
• Consequence: KPTN NM_007059.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -2.17
• 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

ENSG00000287896 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BP6: Variant 19-47476658-G-A is Benign according to our data. Variant chr19-47476658-G-A is described in ClinVar as Benign. ClinVar VariationId is 474855.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-2.17 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0141 (2134/151576) while in subpopulation AFR AF = 0.0485 (2005/41340). AF 95% confidence interval is 0.0467. There are 43 homozygotes in GnomAd4. There are 1015 alleles in the male GnomAd4 subpopulation. Median coverage is 27. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 43 AR gene

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.1056C>T	p.His352His	synonymous	Exon 11 of 12	NP_008990.2
	KPTN	NM_001291296.2		c.888C>T	p.His296His	synonymous	Exon 9 of 10	NP_001278225.1
	KPTN	NR_111923.2		n.1202C>T		non_coding_transcript_exon	Exon 12 of 13

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KPTN	ENST00000338134.8	TSL:1 MANE Select	c.1056C>T	p.His352His	synonymous	Exon 11 of 12	ENSP00000337850.2
	KPTN	ENST00000594208.5	TSL:2	n.*690C>T		non_coding_transcript_exon	Exon 12 of 13	ENSP00000470364.1
	ENSG00000287896	ENST00000669287.1		n.265G>A		non_coding_transcript_exon	Exon 2 of 2

Frequencies

GnomAD3 genomes AF: 0.0140 AC: 2122 AN: 151456 Hom.: 42 Cov.: 27

Gnomad AFR AF: 0.0484

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00548

Gnomad ASJ AF: 0.00231

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000209

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000280

Gnomad OTH AF: 0.00867

GnomAD2 exomes AF: 0.00338 AC: 833 AN: 246242 AF XY: 0.00259

Gnomad AFR exome AF: 0.0463

Gnomad AMR exome AF: 0.00204

Gnomad ASJ exome AF: 0.00221

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000314

Gnomad OTH exome AF: 0.00100

GnomAD4 exome AF: 0.00170 AC: 2480 AN: 1461328 Hom.: 42 Cov.: 31 AF XY: 0.00150 AC XY: 1087 AN XY: 726926

African (AFR) AF: 0.0498 AC: 1667 AN: 33472

American (AMR) AF: 0.00260 AC: 116 AN: 44652

Ashkenazi Jewish (ASJ) AF: 0.00310 AC: 81 AN: 26112

East Asian (EAS) AF: 0.00 AC: 0 AN: 39680

South Asian (SAS) AF: 0.000197 AC: 17 AN: 86164

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53306

Middle Eastern (MID) AF: 0.00329 AC: 19 AN: 5768

European-Non Finnish (NFE) AF: 0.000299 AC: 332 AN: 1111808

Other (OTH) AF: 0.00411 AC: 248 AN: 60366

GnomAD4 genome AF: 0.0141 AC: 2134 AN: 151576 Hom.: 43 Cov.: 27 AF XY: 0.0137 AC XY: 1015 AN XY: 74038

African (AFR) AF: 0.0485 AC: 2005 AN: 41340

American (AMR) AF: 0.00547 AC: 83 AN: 15172

Ashkenazi Jewish (ASJ) AF: 0.00231 AC: 8 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5014

South Asian (SAS) AF: 0.000209 AC: 1 AN: 4774

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10570

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

European-Non Finnish (NFE) AF: 0.000280 AC: 19 AN: 67934

Other (OTH) AF: 0.00857 AC: 18 AN: 2100

Alfa AF: 0.00723 Hom.: 13

Bravo AF: 0.0163

Asia WGS AF: 0.00260 AC: 9 AN: 3478

EpiCase AF: 0.000491

EpiControl AF: 0.000595

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	KPTN-related disorder (1)
-	-	1	Macrocephaly-developmental delay syndrome (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	0.072
DANN	Benign	0.72
PhyloP100		-2.2
Mutation Taster		=100/0	polymorphism

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: rs73940855; hg19: chr19-47979915;