9-740769-CTTTTTTTTTTT-CTTTT

Variant names:

• chr9-740769-CTTTTTTT-C
• rs58169581
• NM_015158.5:c.3554-11_3554-5delTTTTTTT

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP6_Moderate BA1

The NM_015158.5(KANK1):​c.3554-11_3554-5delTTTTTTT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.065 in 1,461,882 control chromosomes in the GnomAD database, including 1,535 homozygotes. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.081 (690 hom., cov: 0)
  • Exomes 𝑓: 0.063 (845 hom.)
• Consequence: KANK1 NM_015158.5 splice_region, intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 3.56
• 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 -10 ACMG points.

• BP6: Variant 9-740769-CTTTTTTT-C is Benign according to our data. Variant chr9-740769-CTTTTTTT-C is described in ClinVar as Benign. ClinVar VariationId is 1269588.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.161 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KANK1	NM_015158.5	c.3554-11_3554-5delTTTTTTT		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_3554-16delTTTTTTT		intron_variant	Intron 8 of 11	1	NM_015158.5	ENSP00000371734.2

Frequencies

GnomAD3 genomes AF: 0.0813 AC: 11756 AN: 144642 Hom.: 691 Cov.: 0

Gnomad AFR AF: 0.164

Gnomad AMI AF: 0.0421

Gnomad AMR AF: 0.0499

Gnomad ASJ AF: 0.0405

Gnomad EAS AF: 0.00166

Gnomad SAS AF: 0.122

Gnomad FIN AF: 0.0535

Gnomad MID AF: 0.107

Gnomad NFE AF: 0.0479

Gnomad OTH AF: 0.0717

GnomAD2 exomes AF: 0.0953 AC: 14494 AN: 152038 AF XY: 0.0987

Gnomad AFR exome AF: 0.212

Gnomad AMR exome AF: 0.0528

Gnomad ASJ exome AF: 0.0681

Gnomad EAS exome AF: 0.00766

Gnomad FIN exome AF: 0.0920

Gnomad NFE exome AF: 0.0819

Gnomad OTH exome AF: 0.0855

GnomAD4 exome AF: 0.0632 AC: 83259 AN: 1317194 Hom.: 845 AF XY: 0.0656 AC XY: 42929 AN XY: 654110

African (AFR) AF: 0.176 AC: 5116 AN: 29142

American (AMR) AF: 0.0446 AC: 1486 AN: 33342

Ashkenazi Jewish (ASJ) AF: 0.0469 AC: 1081 AN: 23040

East Asian (EAS) AF: 0.00268 AC: 101 AN: 37686

South Asian (SAS) AF: 0.138 AC: 10164 AN: 73862

European-Finnish (FIN) AF: 0.0682 AC: 3068 AN: 45014

Middle Eastern (MID) AF: 0.0663 AC: 347 AN: 5230

European-Non Finnish (NFE) AF: 0.0573 AC: 58168 AN: 1015378

Other (OTH) AF: 0.0684 AC: 3728 AN: 54500

GnomAD4 genome AF: 0.0814 AC: 11778 AN: 144688 Hom.: 690 Cov.: 0 AF XY: 0.0812 AC XY: 5689 AN XY: 70080

African (AFR) AF: 0.164 AC: 6513 AN: 39710

American (AMR) AF: 0.0498 AC: 710 AN: 14252

Ashkenazi Jewish (ASJ) AF: 0.0405 AC: 134 AN: 3306

East Asian (EAS) AF: 0.00166 AC: 8 AN: 4810

South Asian (SAS) AF: 0.123 AC: 563 AN: 4584

European-Finnish (FIN) AF: 0.0535 AC: 488 AN: 9126

Middle Eastern (MID) AF: 0.123 AC: 34 AN: 276

European-Non Finnish (NFE) AF: 0.0479 AC: 3148 AN: 65742

Other (OTH) AF: 0.0714 AC: 143 AN: 2004

Alfa AF: 0.0506 Hom.: 333

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Jan 16, 2020

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		3.6
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; COSMIC: COSV66528272;