chr9-713245-A-G

Variant names:

• chr9-713245-A-G
• rs1057520089
• NM_015158.5:c.2479A>G

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_015158.5(KANK1):​c.2479A>G​(p.Ile827Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000206 in 1,456,712 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: KANK1 NM_015158.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.22
• Publications: 0 publications found

Genes affected

KANK1 (HGNC:19309): (KN motif and ankyrin repeat domains 1) The protein encoded by this gene belongs to the Kank family of proteins, which contain multiple ankyrin repeat domains. This family member functions in cytoskeleton formation by regulating actin polymerization. This gene is a candidate tumor suppressor for renal cell carcinoma. Mutations in this gene cause cerebral palsy spastic quadriplegic type 2, a central nervous system development disorder. A t(5;9) translocation results in fusion of the platelet-derived growth factor receptor beta gene (PDGFRB) on chromosome 5 with this gene in a myeloproliferative neoplasm featuring severe thrombocythemia. Alternative splicing of this gene results in multiple transcript variants. A related pseudogene has been identified on chromosome 20. [provided by RefSeq, Dec 2014]

KANK1 Gene-Disease associations (from GenCC):

• spastic quadriplegic cerebral palsy

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• cerebral palsy, spastic quadriplegic, 2

  Inheritance: Unknown, AD Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_015158.5. 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
	KANK1	NM_015158.5	MANE Select	c.2479A>G	p.Ile827Val	missense	Exon 3 of 12	NP_055973.2
	KANK1	NM_001256876.3		c.2479A>G	p.Ile827Val	missense	Exon 7 of 16	NP_001243805.1
	KANK1	NM_001256877.3		c.2479A>G	p.Ile827Val	missense	Exon 4 of 13	NP_001243806.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KANK1	ENST00000382297.7	TSL:1 MANE Select	c.2479A>G	p.Ile827Val	missense	Exon 3 of 12	ENSP00000371734.2
	KANK1	ENST00000382303.5	TSL:1	c.2479A>G	p.Ile827Val	missense	Exon 7 of 16	ENSP00000371740.1
	KANK1	ENST00000382293.7	TSL:1	c.2005A>G	p.Ile669Val	missense	Exon 2 of 11	ENSP00000371730.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000814 AC: 2 AN: 245726 AF XY: 0.0000151

Gnomad AFR exome AF: 0.0000617

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000900

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000206 AC: 3 AN: 1456712 Hom.: 0 Cov.: 33 AF XY: 0.00000414 AC XY: 3 AN XY: 724300

African (AFR) AF: 0.0000299 AC: 1 AN: 33400

American (AMR) AF: 0.00 AC: 0 AN: 44326

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25572

East Asian (EAS) AF: 0.00 AC: 0 AN: 39696

South Asian (SAS) AF: 0.00 AC: 0 AN: 84908

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53210

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5720

European-Non Finnish (NFE) AF: 9.01e-7 AC: 1 AN: 1109720

Other (OTH) AF: 0.0000166 AC: 1 AN: 60160

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Nov 02, 2016

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Benign	-0.27
CADD	Uncertain	24
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.023	T
Eigen	Pathogenic	0.76
Eigen_PC	Pathogenic	0.72
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Benign	0.0073	T
MetaRNN	Uncertain	0.48	T
MetaSVM	Benign	-0.93	T
MutationAssessor	Pathogenic	3.1	M
PhyloP100		9.2
PrimateAI	Uncertain	0.49	T
PROVEAN	Benign	-0.35	N
REVEL	Benign	0.23
Sift	Benign	0.039	D
Sift4G	Benign	0.075	T
Polyphen		1.0	D
Vest4		0.61
MutPred		0.19		Loss of methylation at K832 (P = 0.1031)
MVP		0.33
ClinPred		0.58	D
GERP RS		5.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.099
gMVP		0.35
Mutation Taster		=74/26	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: rs1057520089; hg19: chr9-713245;