9-740769-CTTTTTTTTTTT-CTTTTTTTTTTTT

Variant names:

• chr9-740769-C-CT
• rs58169581
• NM_015158.5:c.3554-5dupT

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BS1 BS2

The NM_015158.5(KANK1):​c.3554-5dupT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. 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 0.0096 (13 hom., cov: 0)
  • Exomes 𝑓: 0.022 (3 hom.)
• Consequence: KANK1 NM_015158.5 splice_region, intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.110
• 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 -8 ACMG points.

• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.00958 (1387/144724) while in subpopulation EAS AF = 0.0408 (196/4808). AF 95% confidence interval is 0.0361. There are 13 homozygotes in GnomAd4. There are 765 alleles in the male GnomAd4 subpopulation. Median coverage is 0. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 13 Unknown,AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KANK1	NM_015158.5	c.3554-5dupT		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.3554-23_3554-22insT		intron_variant	Intron 8 of 11	1	NM_015158.5	ENSP00000371734.2

Frequencies

GnomAD3 genomes AF: 0.00960 AC: 1389 AN: 144678 Hom.: 13 Cov.: 0

Gnomad AFR AF: 0.00969

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0116

Gnomad ASJ AF: 0.00272

Gnomad EAS AF: 0.0409

Gnomad SAS AF: 0.00674

Gnomad FIN AF: 0.0288

Gnomad MID AF: 0.00333

Gnomad NFE AF: 0.00491

Gnomad OTH AF: 0.00802

GnomAD2 exomes AF: 0.0229 AC: 3483 AN: 152038 AF XY: 0.0214

Gnomad AFR exome AF: 0.0223

Gnomad AMR exome AF: 0.0394

Gnomad ASJ exome AF: 0.0242

Gnomad EAS exome AF: 0.0612

Gnomad FIN exome AF: 0.0130

Gnomad NFE exome AF: 0.0175

Gnomad OTH exome AF: 0.0273

GnomAD4 exome AF: 0.0219 AC: 29574 AN: 1349242 Hom.: 3 Cov.: 0 AF XY: 0.0215 AC XY: 14433 AN XY: 670646

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

African (AFR) AF: 0.0224 AC: 662 AN: 29608

American (AMR) AF: 0.0334 AC: 1116 AN: 33414

Ashkenazi Jewish (ASJ) AF: 0.0265 AC: 616 AN: 23230

East Asian (EAS) AF: 0.0498 AC: 1868 AN: 37514

South Asian (SAS) AF: 0.0200 AC: 1523 AN: 76138

European-Finnish (FIN) AF: 0.0224 AC: 1028 AN: 45930

Middle Eastern (MID) AF: 0.0173 AC: 92 AN: 5328

European-Non Finnish (NFE) AF: 0.0204 AC: 21289 AN: 1042506

Other (OTH) AF: 0.0248 AC: 1380 AN: 55574

⚠️ 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: 0.00958 AC: 1387 AN: 144724 Hom.: 13 Cov.: 0 AF XY: 0.0109 AC XY: 765 AN XY: 70086

African (AFR) AF: 0.00969 AC: 385 AN: 39714

American (AMR) AF: 0.0116 AC: 165 AN: 14258

Ashkenazi Jewish (ASJ) AF: 0.00272 AC: 9 AN: 3308

East Asian (EAS) AF: 0.0408 AC: 196 AN: 4808

South Asian (SAS) AF: 0.00654 AC: 30 AN: 4590

European-Finnish (FIN) AF: 0.0288 AC: 263 AN: 9122

Middle Eastern (MID) AF: 0.00362 AC: 1 AN: 276

European-Non Finnish (NFE) AF: 0.00491 AC: 323 AN: 65766

Other (OTH) AF: 0.00749 AC: 15 AN: 2004

Alfa AF: 0.0112 Hom.: 333

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.11
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;