9-740769-CTTTTTTTTTTT-CTTTTT

Variant names:

• chr9-740769-CTTTTTT-C
• rs58169581
• NM_015158.5:c.3554-10_3554-5delTTTTTT

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

The NM_015158.5(KANK1):​c.3554-10_3554-5delTTTTTT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.33 (7923 hom., cov: 0)
  • Exomes 𝑓: 0.30 (17032 hom.)
  • Failed GnomAD Quality Control
• Consequence: KANK1 NM_015158.5 splice_region, intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.735
• 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: Benign. The variant received -16 ACMG points.

• BP6: Variant 9-740769-CTTTTTT-C is Benign according to our data. Variant chr9-740769-CTTTTTT-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 446056.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.371 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KANK1	NM_015158.5	c.3554-10_3554-5delTTTTTT		splice_region_variant, intron_variant	Intron 8 of 11	ENST00000382297.7	NP_055973.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KANK1	ENST00000382297.7	c.3554-22_3554-17delTTTTTT		intron_variant	Intron 8 of 11	1	NM_015158.5	ENSP00000371734.2

Frequencies

GnomAD3 genomes AF: 0.334 AC: 48269 AN: 144644 Hom.: 7927 Cov.: 0

Gnomad AFR AF: 0.322

Gnomad AMI AF: 0.453

Gnomad AMR AF: 0.233

Gnomad ASJ AF: 0.220

Gnomad EAS AF: 0.180

Gnomad SAS AF: 0.363

Gnomad FIN AF: 0.349

Gnomad MID AF: 0.350

Gnomad NFE AF: 0.375

Gnomad OTH AF: 0.304

GnomAD2 exomes AF: 0.333 AC: 50672 AN: 152038 AF XY: 0.339

Gnomad AFR exome AF: 0.321

Gnomad AMR exome AF: 0.233

Gnomad ASJ exome AF: 0.276

Gnomad EAS exome AF: 0.216

Gnomad FIN exome AF: 0.381

Gnomad NFE exome AF: 0.368

Gnomad OTH exome AF: 0.330

GnomAD4 exome Data not reliable, filtered out with message: InbreedingCoeff AF: 0.299 AC: 403410 AN: 1351196 Hom.: 17032 AF XY: 0.299 AC XY: 201157 AN XY: 671786

African (AFR) AF: 0.284 AC: 8402 AN: 29628

American (AMR) AF: 0.187 AC: 6283 AN: 33622

Ashkenazi Jewish (ASJ) AF: 0.203 AC: 4726 AN: 23316

East Asian (EAS) AF: 0.131 AC: 4946 AN: 37886

South Asian (SAS) AF: 0.312 AC: 23808 AN: 76256

European-Finnish (FIN) AF: 0.304 AC: 14031 AN: 46186

Middle Eastern (MID) AF: 0.323 AC: 1731 AN: 5358

European-Non Finnish (NFE) AF: 0.311 AC: 324019 AN: 1043202

Other (OTH) AF: 0.277 AC: 15464 AN: 55742

GnomAD4 genome AF: 0.334 AC: 48262 AN: 144692 Hom.: 7923 Cov.: 0 AF XY: 0.330 AC XY: 23122 AN XY: 70078

African (AFR) AF: 0.322 AC: 12791 AN: 39718

American (AMR) AF: 0.233 AC: 3322 AN: 14256

Ashkenazi Jewish (ASJ) AF: 0.220 AC: 728 AN: 3312

East Asian (EAS) AF: 0.179 AC: 862 AN: 4808

South Asian (SAS) AF: 0.364 AC: 1667 AN: 4584

European-Finnish (FIN) AF: 0.349 AC: 3182 AN: 9128

Middle Eastern (MID) AF: 0.330 AC: 91 AN: 276

European-Non Finnish (NFE) AF: 0.375 AC: 24616 AN: 65730

Other (OTH) AF: 0.302 AC: 606 AN: 2004

Alfa AF: 0.208 Hom.: 333

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Dec 18, 2019

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 19, 2017

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

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.73
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs58169581; hg19: chr9-740769;