9-740769-CTTTTTTTTTTT-CTTTTTTTTT

Variant names:

• chr9-740769-CTT-C
• rs58169581
• NM_015158.5:c.3554-6_3554-5delTT

Variant summary

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

The NM_015158.5(KANK1):​c.3554-6_3554-5delTT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00966 in 1,465,332 control chromosomes in the GnomAD database, with no homozygous occurrence. 1/1 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.00017 (0 hom., cov: 0)
  • Exomes 𝑓: 0.011 (0 hom.)
• Consequence: KANK1 NM_015158.5 splice_region, intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.147
• 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 0 ACMG points.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KANK1	NM_015158.5	c.3554-6_3554-5delTT		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_3554-21delTT		intron_variant	Intron 8 of 11	1	NM_015158.5	ENSP00000371734.2

Frequencies

GnomAD3 genomes AF: 0.000166 AC: 24 AN: 144666 Hom.: 0 Cov.: 0

Gnomad AFR AF: 0.000151

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000211

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00121

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000608

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0176 AC: 2683 AN: 152038 AF XY: 0.0168

Gnomad AFR exome AF: 0.00736

Gnomad AMR exome AF: 0.0353

Gnomad ASJ exome AF: 0.0264

Gnomad EAS exome AF: 0.0371

Gnomad FIN exome AF: 0.00978

Gnomad NFE exome AF: 0.0142

Gnomad OTH exome AF: 0.0203

GnomAD4 exome AF: 0.0107 AC: 14130 AN: 1320620 Hom.: 0 AF XY: 0.0111 AC XY: 7269 AN XY: 656540

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

African (AFR) AF: 0.00608 AC: 179 AN: 29460

American (AMR) AF: 0.0297 AC: 960 AN: 32294

Ashkenazi Jewish (ASJ) AF: 0.0210 AC: 471 AN: 22444

East Asian (EAS) AF: 0.0289 AC: 1026 AN: 35528

South Asian (SAS) AF: 0.0122 AC: 915 AN: 75180

European-Finnish (FIN) AF: 0.0126 AC: 569 AN: 45134

Middle Eastern (MID) AF: 0.00911 AC: 48 AN: 5270

European-Non Finnish (NFE) AF: 0.00913 AC: 9322 AN: 1021056

Other (OTH) AF: 0.0118 AC: 640 AN: 54254

⚠️ 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: 0.000166 AC: 24 AN: 144712 Hom.: 0 Cov.: 0 AF XY: 0.000200 AC XY: 14 AN XY: 70088

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

African (AFR) AF: 0.000151 AC: 6 AN: 39732

American (AMR) AF: 0.000210 AC: 3 AN: 14260

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3308

East Asian (EAS) AF: 0.00 AC: 0 AN: 4808

South Asian (SAS) AF: 0.00 AC: 0 AN: 4588

European-Finnish (FIN) AF: 0.00121 AC: 11 AN: 9098

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

European-Non Finnish (NFE) AF: 0.0000608 AC: 4 AN: 65760

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

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.0131 Hom.: 333

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.15
Mutation Taster		=100/0	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: rs58169581; hg19: chr9-740769;