9-740769-C-CTTTT

Variant names:

• chr9-740769-C-CTTTT
• rs58169581
• NM_015158.5:c.3554-8_3554-5dupTTTT

Variant summary

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

The NM_015158.5(KANK1):​c.3554-8_3554-5dupTTTT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.000028 (0 hom., cov: 0)
  • Exomes 𝑓: 0.000018 (0 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), Ambry Genetics, G2P

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

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.3554-8_3554-5dupTTTT		splice_region intron	N/A	NP_055973.2	Q14678-1
	KANK1	NM_001256876.3		c.3554-8_3554-5dupTTTT		splice_region intron	N/A	NP_001243805.1	Q14678-1
	KANK1	NM_001256877.3		c.3554-8_3554-5dupTTTT		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.3554-23_3554-22insTTTT		intron	N/A	ENSP00000371734.2	Q14678-1
	KANK1	ENST00000382303.5	TSL:1	c.3554-23_3554-22insTTTT		intron	N/A	ENSP00000371740.1	Q14678-1
	KANK1	ENST00000382293.7	TSL:1	c.3080-23_3080-22insTTTT		intron	N/A	ENSP00000371730.3	Q14678-2

Frequencies

GnomAD3 genomes AF: 0.0000276 AC: 4 AN: 144716 Hom.: 0 Cov.: 0

Gnomad AFR AF: 0.000101

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.0000176 AC: 24 AN: 1361092 Hom.: 0 Cov.: 0 AF XY: 0.0000177 AC XY: 12 AN XY: 676636

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

African (AFR) AF: 0.000167 AC: 5 AN: 29954

American (AMR) AF: 0.0000297 AC: 1 AN: 33722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23404

East Asian (EAS) AF: 0.0000527 AC: 2 AN: 37942

South Asian (SAS) AF: 0.0000130 AC: 1 AN: 76892

European-Finnish (FIN) AF: 0.0000431 AC: 2 AN: 46380

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5380

European-Non Finnish (NFE) AF: 0.00000856 AC: 9 AN: 1051298

Other (OTH) AF: 0.0000713 AC: 4 AN: 56120

⚠️ 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: 0.0000276 AC: 4 AN: 144716 Hom.: 0 Cov.: 0 AF XY: 0.00 AC XY: 0 AN XY: 70042

African (AFR) AF: 0.000101 AC: 4 AN: 39648

American (AMR) AF: 0.00 AC: 0 AN: 14246

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3310

East Asian (EAS) AF: 0.00 AC: 0 AN: 4822

South Asian (SAS) AF: 0.00 AC: 0 AN: 4600

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 9134

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 300

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 65784

Other (OTH) AF: 0.00 AC: 0 AN: 1994

Alfa AF: 0.00 Hom.: 333

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.11

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs58169581; hg19: chr9-740769;