chr9-676741-A-G

Variant names:

• chr9-676741-A-G
• rs10975740
• NM_015158.5:c.-83-149A>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.-83-149A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.076 in 443,038 control chromosomes in the GnomAD database, including 1,536 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.070 (461 hom., cov: 32)
  • Exomes 𝑓: 0.079 (1075 hom.)
• Consequence: KANK1 NM_015158.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.61
• Publications: 2 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=-0.91).
• BP6: Variant 9-676741-A-G is Benign according to our data. Variant chr9-676741-A-G is described in ClinVar as [Benign]. Clinvar id is 1279682.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0918 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KANK1	NM_015158.5	c.-83-149A>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.-83-149A>G		intron_variant	Intron 1 of 11	1	NM_015158.5	ENSP00000371734.2

Frequencies

GnomAD3 genomes AF: 0.0698 AC: 10616 AN: 152106 Hom.: 460 Cov.: 32

Gnomad AFR AF: 0.0373

Gnomad AMI AF: 0.0559

Gnomad AMR AF: 0.0523

Gnomad ASJ AF: 0.0821

Gnomad EAS AF: 0.0269

Gnomad SAS AF: 0.0566

Gnomad FIN AF: 0.0929

Gnomad MID AF: 0.0728

Gnomad NFE AF: 0.0937

Gnomad OTH AF: 0.0707

GnomAD4 exome AF: 0.0792 AC: 23027 AN: 290814 Hom.: 1075 AF XY: 0.0781 AC XY: 11967 AN XY: 153280

African (AFR) AF: 0.0321 AC: 253 AN: 7872

American (AMR) AF: 0.0450 AC: 406 AN: 9014

Ashkenazi Jewish (ASJ) AF: 0.0771 AC: 723 AN: 9372

East Asian (EAS) AF: 0.0473 AC: 954 AN: 20182

South Asian (SAS) AF: 0.0539 AC: 1544 AN: 28642

European-Finnish (FIN) AF: 0.0865 AC: 1769 AN: 20448

Middle Eastern (MID) AF: 0.0886 AC: 117 AN: 1320

European-Non Finnish (NFE) AF: 0.0903 AC: 15974 AN: 176860

Other (OTH) AF: 0.0752 AC: 1287 AN: 17104

GnomAD4 genome AF: 0.0698 AC: 10628 AN: 152224 Hom.: 461 Cov.: 32 AF XY: 0.0693 AC XY: 5156 AN XY: 74434

African (AFR) AF: 0.0372 AC: 1547 AN: 41532

American (AMR) AF: 0.0521 AC: 797 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.0821 AC: 285 AN: 3472

East Asian (EAS) AF: 0.0272 AC: 141 AN: 5186

South Asian (SAS) AF: 0.0581 AC: 280 AN: 4818

European-Finnish (FIN) AF: 0.0929 AC: 985 AN: 10608

Middle Eastern (MID) AF: 0.0782 AC: 23 AN: 294

European-Non Finnish (NFE) AF: 0.0937 AC: 6371 AN: 67998

Other (OTH) AF: 0.0700 AC: 148 AN: 2114

Alfa AF: 0.0604 Hom.: 142

Bravo AF: 0.0638

Asia WGS AF: 0.0440 AC: 151 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Feb 01, 2020

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	0.28
DANN	Benign	0.24
PhyloP100		-1.6
PromoterAI		0.026	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: rs10975740; hg19: chr9-676741;