NM_007059.4:c.786G>C

Variant names:

• chr19-47479864-C-G
• rs371354579
• NM_007059.4:c.786G>C

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.786G>C​(p.Lys262Asn) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 18/23 in silico tools predict 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. Synonymous variant affecting the same amino acid position (i.e. K262K) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 31)
• Consequence: KPTN NM_007059.4 missense, splice_region
• Scores: Splicing: ADA: 0.0006333
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.740
• 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 (MetaRNN=0.065897584).

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.786G>C	p.Lys262Asn	missense splice_region	Exon 8 of 12	NP_008990.2
	KPTN	NM_001291296.2		c.618G>C	p.Lys206Asn	missense splice_region	Exon 6 of 10	NP_001278225.1
	KPTN	NR_111923.2		n.932G>C		splice_region non_coding_transcript_exon	Exon 9 of 13

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KPTN	ENST00000338134.8	TSL:1 MANE Select	c.786G>C	p.Lys262Asn	missense splice_region	Exon 8 of 12	ENSP00000337850.2
	KPTN	ENST00000595554.1	TSL:3	c.618G>C	p.Lys206Asn	missense splice_region	Exon 6 of 8	ENSP00000469446.1
	KPTN	ENST00000600271.5	TSL:5	c.66G>C	p.Lys22Asn	missense splice_region	Exon 9 of 10	ENSP00000472291.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.37	T
BayesDel_noAF	Benign	-0.77
CADD	Benign	1.6
DANN	Benign	0.95
DEOGEN2	Benign	0.013	T
Eigen	Benign	-1.0
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.054	N
LIST_S2	Benign	0.29	T
M_CAP	Benign	0.0022	T
MetaRNN	Benign	0.066	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.0	N
PhyloP100		-0.74
PrimateAI	Benign	0.25	T
PROVEAN	Benign	0.30	N
REVEL	Benign	0.018
Sift	Benign	0.47	T
Sift4G	Benign	0.48	T
Polyphen		0.0060	B
Vest4		0.15
MutPred		0.30		Loss of ubiquitination at K262 (P = 0.0041)
MVP		0.22
MPC		0.48
ClinPred		0.069	T
GERP RS		-1.7
Varity_R		0.063
gMVP		0.32
Mutation Taster		=94/6	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00063
dbscSNV1_RF	Benign	0.034
SpliceAI score (max)		0.020		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: rs371354579; hg19: chr19-47983121;