NM_007059.4:c.761T>C

Variant names:

• chr19-47479889-A-G
• rs200513352
• NM_007059.4:c.761T>C

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4_Strong BP6

The NM_007059.4(KPTN):​c.761T>C​(p.Ile254Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000425 in 1,613,504 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00090 (1 hom., cov: 31)
  • Exomes 𝑓: 0.00037 (1 hom.)
• Consequence: KPTN NM_007059.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:2
• Conservation: PhyloP100: 2.54
• Publications: 2 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 -5 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.012604177).
• BP6: Variant 19-47479889-A-G is Benign according to our data. Variant chr19-47479889-A-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 435676.

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.761T>C	p.Ile254Thr	missense	Exon 8 of 12	NP_008990.2
	KPTN	NM_001291296.2		c.593T>C	p.Ile198Thr	missense	Exon 6 of 10	NP_001278225.1
	KPTN	NR_111923.2		n.907T>C		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.761T>C	p.Ile254Thr	missense	Exon 8 of 12	ENSP00000337850.2
	KPTN	ENST00000914957.1		c.761T>C	p.Ile254Thr	missense	Exon 8 of 12	ENSP00000585016.1
	KPTN	ENST00000968682.1		c.593T>C	p.Ile198Thr	missense	Exon 6 of 10	ENSP00000638741.1

Frequencies

GnomAD3 genomes AF: 0.000902 AC: 137 AN: 151946 Hom.: 1 Cov.: 31

Gnomad AFR AF: 0.000871

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00432

Gnomad ASJ AF: 0.000865

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000383

Gnomad OTH AF: 0.00239

GnomAD2 exomes AF: 0.000599 AC: 149 AN: 248580 AF XY: 0.000600

Gnomad AFR exome AF: 0.000715

Gnomad AMR exome AF: 0.00212

Gnomad ASJ exome AF: 0.00110

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000426

Gnomad OTH exome AF: 0.000994

GnomAD4 exome AF: 0.000375 AC: 548 AN: 1461440 Hom.: 1 Cov.: 32 AF XY: 0.000370 AC XY: 269 AN XY: 727070

African (AFR) AF: 0.000508 AC: 17 AN: 33472

American (AMR) AF: 0.00221 AC: 99 AN: 44698

Ashkenazi Jewish (ASJ) AF: 0.00184 AC: 48 AN: 26124

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.00 AC: 0 AN: 86218

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53300

Middle Eastern (MID) AF: 0.000867 AC: 5 AN: 5766

European-Non Finnish (NFE) AF: 0.000306 AC: 340 AN: 1111790

Other (OTH) AF: 0.000646 AC: 39 AN: 60374

GnomAD4 genome AF: 0.000901 AC: 137 AN: 152064 Hom.: 1 Cov.: 31 AF XY: 0.000955 AC XY: 71 AN XY: 74342

African (AFR) AF: 0.000869 AC: 36 AN: 41446

American (AMR) AF: 0.00431 AC: 66 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.000865 AC: 3 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5162

South Asian (SAS) AF: 0.000208 AC: 1 AN: 4818

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

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

European-Non Finnish (NFE) AF: 0.000383 AC: 26 AN: 67944

Other (OTH) AF: 0.00237 AC: 5 AN: 2110

Alfa AF: 0.000516 Hom.: 1

Bravo AF: 0.000956

ESP6500AA AF: 0.00100 AC: 4

ESP6500EA AF: 0.000483 AC: 4

ExAC AF: 0.000339 AC: 41

EpiCase AF: 0.000600

EpiControl AF: 0.000356

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.095
BayesDel_addAF	Benign	-0.45	T
BayesDel_noAF	Benign	-0.41
CADD	Benign	20
DANN	Benign	0.92
DEOGEN2	Benign	0.023	T
Eigen	Benign	-0.45
Eigen_PC	Benign	-0.25
FATHMM_MKL	Uncertain	0.77	D
LIST_S2	Benign	0.78	T
M_CAP	Benign	0.0077	T
MetaRNN	Benign	0.013	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.9	L
PhyloP100		2.5
PrimateAI	Uncertain	0.62	T
PROVEAN	Benign	0.070	N
REVEL	Benign	0.076
Sift	Benign	0.85	T
Sift4G	Benign	0.78	T
Polyphen		0.0	B
Vest4		0.33
MVP		0.38
MPC		0.49
ClinPred		0.010	T
GERP RS		4.2
Varity_R		0.050
gMVP		0.37
Mutation Taster		=83/17	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
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: rs200513352; hg19: chr19-47983146;