19-47484154-C-T

Variant names:

• chr19-47484154-C-T
• rs549545571
• NM_007059.4:c.7G>A

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_007059.4(KPTN):​c.7G>A​(p.Gly3Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000217 in 1,596,638 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.000039 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00024 (0 hom.)
• Consequence: KPTN NM_007059.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 2.27
• 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]

NAPA-AS1 (HGNC:44118): (NAPA antisense RNA 1)

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.08496699).

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.7G>A	p.Gly3Arg	missense	Exon 1 of 12	NP_008990.2
	KPTN	NM_001291296.2		c.7G>A	p.Gly3Arg	missense	Exon 1 of 10	NP_001278225.1
	KPTN	NR_111923.2		n.66G>A		non_coding_transcript_exon	Exon 1 of 13

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KPTN	ENST00000338134.8	TSL:1 MANE Select	c.7G>A	p.Gly3Arg	missense	Exon 1 of 12	ENSP00000337850.2
	KPTN	ENST00000914957.1		c.7G>A	p.Gly3Arg	missense	Exon 1 of 12	ENSP00000585016.1
	KPTN	ENST00000968682.1		c.7G>A	p.Gly3Arg	missense	Exon 1 of 10	ENSP00000638741.1

Frequencies

GnomAD3 genomes AF: 0.0000395 AC: 6 AN: 151934 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

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: 0.0000736

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000961 AC: 22 AN: 228874 AF XY: 0.0000946

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000439

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000567

Gnomad OTH exome AF: 0.000173

GnomAD4 exome AF: 0.000236 AC: 341 AN: 1444586 Hom.: 0 Cov.: 31 AF XY: 0.000228 AC XY: 164 AN XY: 718836

African (AFR) AF: 0.00 AC: 0 AN: 33390

American (AMR) AF: 0.000359 AC: 16 AN: 44588

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26038

East Asian (EAS) AF: 0.00 AC: 0 AN: 39622

South Asian (SAS) AF: 0.00 AC: 0 AN: 86086

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 38688

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5678

European-Non Finnish (NFE) AF: 0.000285 AC: 316 AN: 1110334

Other (OTH) AF: 0.000150 AC: 9 AN: 60162

GnomAD4 genome AF: 0.0000395 AC: 6 AN: 152052 Hom.: 0 Cov.: 32 AF XY: 0.0000538 AC XY: 4 AN XY: 74326

African (AFR) AF: 0.00 AC: 0 AN: 41458

American (AMR) AF: 0.0000654 AC: 1 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5140

South Asian (SAS) AF: 0.00 AC: 0 AN: 4814

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10608

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 290

European-Non Finnish (NFE) AF: 0.0000736 AC: 5 AN: 67964

Other (OTH) AF: 0.00 AC: 0 AN: 2108

Alfa AF: 0.0000812 Hom.: 0

Bravo AF: 0.0000567

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.000259 AC: 1

ExAC AF: 0.0000927 AC: 11

EpiCase AF: 0.000109

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	-	Inborn genetic diseases (1)
-	1	-	Macrocephaly-developmental delay syndrome (1)
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.34
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Benign	-0.18
CADD	Pathogenic	27
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.022	T
Eigen	Uncertain	0.35
Eigen_PC	Uncertain	0.36
FATHMM_MKL	Benign	0.43	N
LIST_S2	Benign	0.82	T
M_CAP	Benign	0.050	D
MetaRNN	Benign	0.085	T
MetaSVM	Benign	-0.72	T
MutationAssessor	Benign	0.0	N
PhyloP100		2.3
PrimateAI	Uncertain	0.71	T
PROVEAN	Benign	-0.73	N
REVEL	Uncertain	0.31
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.37
MutPred		0.27		Loss of loop (P = 0.0112)
MVP		0.50
MPC		1.3
ClinPred		0.20	T
GERP RS		4.6
PromoterAI		0.037	Neutral
RBP_binding_hub_radar		1.1
RBP_regulation_power_radar		2.9
Varity_R		0.50
gMVP		0.61
Mutation Taster		=78/22	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: rs549545571; hg19: chr19-47987411;