9-740769-CTTTTTTTTTTT-CTTTTTTTTTT

Variant names:

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

Variant summary

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

The NM_015158.5(KANK1):​c.3554-5delT 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. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0021 (0 hom., cov: 0)
  • Exomes 𝑓: 0.12 (0 hom.)
• Consequence: KANK1 NM_015158.5 splice_region, intron
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• 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), Ambry Genetics, G2P

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• BP6: Variant 9-740769-CT-C is Benign according to our data. Variant chr9-740769-CT-C is described in ClinVar as Likely_benign. ClinVar VariationId is 1316657.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_015158.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KANK1	NM_015158.5	MANE Select	c.3554-5delT		splice_region intron	N/A	NP_055973.2	Q14678-1
	KANK1	NM_001256876.3		c.3554-5delT		splice_region intron	N/A	NP_001243805.1	Q14678-1
	KANK1	NM_001256877.3		c.3554-5delT		splice_region intron	N/A	NP_001243806.1	Q14678-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KANK1	ENST00000382297.7	TSL:1 MANE Select	c.3554-22delT		intron	N/A	ENSP00000371734.2	Q14678-1
	KANK1	ENST00000382303.5	TSL:1	c.3554-22delT		intron	N/A	ENSP00000371740.1	Q14678-1
	KANK1	ENST00000382293.7	TSL:1	c.3080-22delT		intron	N/A	ENSP00000371730.3	Q14678-2

Frequencies

GnomAD3 genomes AF: 0.00206 AC: 298 AN: 144648 Hom.: 0 Cov.: 0

Gnomad AFR AF: 0.00257

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00162

Gnomad ASJ AF: 0.000604

Gnomad EAS AF: 0.00456

Gnomad SAS AF: 0.000652

Gnomad FIN AF: 0.00604

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00132

Gnomad OTH AF: 0.00201

GnomAD2 exomes AF: 0.103 AC: 15668 AN: 152038 AF XY: 0.0997

Gnomad AFR exome AF: 0.0566

Gnomad AMR exome AF: 0.175

Gnomad ASJ exome AF: 0.143

Gnomad EAS exome AF: 0.209

Gnomad FIN exome AF: 0.0699

Gnomad NFE exome AF: 0.0910

Gnomad OTH exome AF: 0.104

GnomAD4 exome AF: 0.116 AC: 147918 AN: 1274658 Hom.: 0 Cov.: 0 AF XY: 0.115 AC XY: 72715 AN XY: 634134

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

African (AFR) AF: 0.0654 AC: 1875 AN: 28678

American (AMR) AF: 0.158 AC: 4990 AN: 31548

Ashkenazi Jewish (ASJ) AF: 0.170 AC: 3680 AN: 21652

East Asian (EAS) AF: 0.246 AC: 8414 AN: 34248

South Asian (SAS) AF: 0.0795 AC: 5859 AN: 73732

European-Finnish (FIN) AF: 0.0967 AC: 4275 AN: 44222

Middle Eastern (MID) AF: 0.118 AC: 597 AN: 5066

European-Non Finnish (NFE) AF: 0.114 AC: 111589 AN: 983066

Other (OTH) AF: 0.127 AC: 6639 AN: 52446

⚠️ 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: 0.00209 AC: 302 AN: 144692 Hom.: 0 Cov.: 0 AF XY: 0.00215 AC XY: 151 AN XY: 70074

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

African (AFR) AF: 0.00264 AC: 105 AN: 39718

American (AMR) AF: 0.00168 AC: 24 AN: 14252

Ashkenazi Jewish (ASJ) AF: 0.000604 AC: 2 AN: 3310

East Asian (EAS) AF: 0.00457 AC: 22 AN: 4810

South Asian (SAS) AF: 0.000654 AC: 3 AN: 4586

European-Finnish (FIN) AF: 0.00604 AC: 55 AN: 9108

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

European-Non Finnish (NFE) AF: 0.00132 AC: 87 AN: 65750

Other (OTH) AF: 0.00200 AC: 4 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: 0.0357 Hom.: 333

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

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; COSMIC: COSV66527205;