rs12685605

Variant names:

• chr9-676745-A-G
• rs12685605
• NM_015158.5:c.-83-145A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_015158.5(KANK1):​c.-83-145A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0303 in 448,500 control chromosomes in the GnomAD database, including 840 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.047 (453 hom., cov: 33)
  • Exomes 𝑓: 0.022 (387 hom.)
• Consequence: KANK1 NM_015158.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.39
• 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

ENSG00000227914 (HGNC:58139):

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BP6: Variant 9-676745-A-G is Benign according to our data. Variant chr9-676745-A-G is described in ClinVar as [Benign]. Clinvar id is 1261637.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.225 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KANK1	NM_015158.5	c.-83-145A>G		intron_variant	Intron 1 of 11	ENST00000382297.7	NP_055973.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KANK1	ENST00000382297.7	c.-83-145A>G		intron_variant	Intron 1 of 11	1	NM_015158.5	ENSP00000371734.2

Frequencies

GnomAD3 genomes AF: 0.0468 AC: 7124 AN: 152134 Hom.: 454 Cov.: 33

Gnomad AFR AF: 0.110

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0339

Gnomad ASJ AF: 0.00922

Gnomad EAS AF: 0.237

Gnomad SAS AF: 0.0356

Gnomad FIN AF: 0.0353

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.00232

Gnomad OTH AF: 0.0383

GnomAD4 exome AF: 0.0219 AC: 6485 AN: 296248 Hom.: 387 AF XY: 0.0216 AC XY: 3369 AN XY: 156102

African (AFR) AF: 0.104 AC: 823 AN: 7882

American (AMR) AF: 0.0372 AC: 342 AN: 9186

Ashkenazi Jewish (ASJ) AF: 0.00994 AC: 95 AN: 9562

East Asian (EAS) AF: 0.143 AC: 2920 AN: 20368

South Asian (SAS) AF: 0.0264 AC: 758 AN: 28700

European-Finnish (FIN) AF: 0.0320 AC: 672 AN: 21000

Middle Eastern (MID) AF: 0.0117 AC: 16 AN: 1370

European-Non Finnish (NFE) AF: 0.00179 AC: 324 AN: 180782

Other (OTH) AF: 0.0308 AC: 535 AN: 17398

GnomAD4 genome AF: 0.0468 AC: 7122 AN: 152252 Hom.: 453 Cov.: 33 AF XY: 0.0478 AC XY: 3559 AN XY: 74456

African (AFR) AF: 0.110 AC: 4558 AN: 41516

American (AMR) AF: 0.0341 AC: 522 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.00922 AC: 32 AN: 3472

East Asian (EAS) AF: 0.236 AC: 1223 AN: 5176

South Asian (SAS) AF: 0.0355 AC: 171 AN: 4822

European-Finnish (FIN) AF: 0.0353 AC: 375 AN: 10616

Middle Eastern (MID) AF: 0.0102 AC: 3 AN: 294

European-Non Finnish (NFE) AF: 0.00232 AC: 158 AN: 68036

Other (OTH) AF: 0.0379 AC: 80 AN: 2112

Alfa AF: 0.0392 Hom.: 130

Bravo AF: 0.0527

Asia WGS AF: 0.127 AC: 443 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Feb 03, 2020

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	0.036
DANN	Benign	0.42
PhyloP100		-1.4
PromoterAI		0.027	Neutral
Mutation Taster		=100/0	polymorphism (auto)

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: rs12685605; hg19: chr9-676745;