9-740769-CTTTTTTTTTTT-CTTTTTT

Variant names:

• chr9-740769-CTTTTT-C
• rs58169581
• NM_015158.5:c.3554-9_3554-5delTTTTT

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP6_Moderate

The NM_015158.5(KANK1):​c.3554-9_3554-5delTTTTT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00754 in 1,472,042 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0013 (0 hom., cov: 0)
  • Exomes 𝑓: 0.0082 (0 hom.)
• Consequence: KANK1 NM_015158.5 splice_region, intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• 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: Likely_benign. The variant received -2 ACMG points.

• BP6: Variant 9-740769-CTTTTT-C is Benign according to our data. Variant chr9-740769-CTTTTT-C is described in ClinVar as Benign. ClinVar VariationId is 931793.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KANK1	NM_015158.5	c.3554-9_3554-5delTTTTT		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_3554-18delTTTTT		intron_variant	Intron 8 of 11	1	NM_015158.5	ENSP00000371734.2

Frequencies

GnomAD3 genomes AF: 0.00131 AC: 190 AN: 144682 Hom.: 0 Cov.: 0

Gnomad AFR AF: 0.00151

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000702

Gnomad ASJ AF: 0.000302

Gnomad EAS AF: 0.000207

Gnomad SAS AF: 0.000435

Gnomad FIN AF: 0.00274

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00152

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00734 AC: 1116 AN: 152038 AF XY: 0.00786

Gnomad AFR exome AF: 0.00664

Gnomad AMR exome AF: 0.00621

Gnomad ASJ exome AF: 0.00495

Gnomad EAS exome AF: 0.00294

Gnomad FIN exome AF: 0.00863

Gnomad NFE exome AF: 0.00760

Gnomad OTH exome AF: 0.00487

GnomAD4 exome AF: 0.00822 AC: 10908 AN: 1327314 Hom.: 0 AF XY: 0.00821 AC XY: 5413 AN XY: 659696

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00776 AC: 228 AN: 29392

American (AMR) AF: 0.00332 AC: 111 AN: 33424

Ashkenazi Jewish (ASJ) AF: 0.00250 AC: 58 AN: 23176

East Asian (EAS) AF: 0.00130 AC: 49 AN: 37760

South Asian (SAS) AF: 0.00890 AC: 666 AN: 74840

European-Finnish (FIN) AF: 0.00667 AC: 303 AN: 45420

Middle Eastern (MID) AF: 0.00510 AC: 27 AN: 5292

European-Non Finnish (NFE) AF: 0.00888 AC: 9084 AN: 1023020

Other (OTH) AF: 0.00695 AC: 382 AN: 54990

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.00131 AC: 190 AN: 144728 Hom.: 0 Cov.: 0 AF XY: 0.00140 AC XY: 98 AN XY: 70096

African (AFR) AF: 0.00151 AC: 60 AN: 39728

American (AMR) AF: 0.0000701 AC: 1 AN: 14256

Ashkenazi Jewish (ASJ) AF: 0.000302 AC: 1 AN: 3310

East Asian (EAS) AF: 0.000208 AC: 1 AN: 4810

South Asian (SAS) AF: 0.000436 AC: 2 AN: 4588

European-Finnish (FIN) AF: 0.00274 AC: 25 AN: 9120

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 276

European-Non Finnish (NFE) AF: 0.00152 AC: 100 AN: 65758

Other (OTH) AF: 0.00 AC: 0 AN: 2004

Alfa AF: 0.00966 Hom.: 333

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Cerebral palsy, spastic quadriplegic, 2 Benign:1

Sep 26, 2018

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was classified as: Benign. The following ACMG criteria were applied in classifying this variant: BS1,BS2. -

Computational scores

Source: dbNSFP v4.3

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

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: COSV66527398;