chr9-676820-A-G

Variant names:

• chr9-676820-A-G
• rs1570474
• NM_015158.5:c.-83-70A>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.-83-70A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.444 in 622,100 control chromosomes in the GnomAD database, including 68,335 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.54 (25296 hom., cov: 32)
  • Exomes 𝑓: 0.41 (43039 hom.)
• Consequence: KANK1 NM_015158.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.0880
• Publications: 6 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=-0.84).
• BP6: Variant 9-676820-A-G is Benign according to our data. Variant chr9-676820-A-G is described in ClinVar as [Benign]. Clinvar id is 1261697.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.836 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KANK1	NM_015158.5	c.-83-70A>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.-83-70A>G		intron_variant	Intron 1 of 11	1	NM_015158.5	ENSP00000371734.2

Frequencies

GnomAD3 genomes AF: 0.539 AC: 81965 AN: 151970 Hom.: 25240 Cov.: 32

Gnomad AFR AF: 0.843

Gnomad AMI AF: 0.447

Gnomad AMR AF: 0.567

Gnomad ASJ AF: 0.405

Gnomad EAS AF: 0.581

Gnomad SAS AF: 0.336

Gnomad FIN AF: 0.471

Gnomad MID AF: 0.481

Gnomad NFE AF: 0.380

Gnomad OTH AF: 0.486

GnomAD4 exome AF: 0.413 AC: 194330 AN: 470012 Hom.: 43039 AF XY: 0.406 AC XY: 101888 AN XY: 251092

African (AFR) AF: 0.836 AC: 10328 AN: 12352

American (AMR) AF: 0.599 AC: 12415 AN: 20734

Ashkenazi Jewish (ASJ) AF: 0.385 AC: 5199 AN: 13504

East Asian (EAS) AF: 0.564 AC: 17538 AN: 31112

South Asian (SAS) AF: 0.325 AC: 14660 AN: 45160

European-Finnish (FIN) AF: 0.447 AC: 18841 AN: 42106

Middle Eastern (MID) AF: 0.421 AC: 1436 AN: 3414

European-Non Finnish (NFE) AF: 0.373 AC: 102955 AN: 276182

Other (OTH) AF: 0.431 AC: 10958 AN: 25448

GnomAD4 genome AF: 0.540 AC: 82081 AN: 152088 Hom.: 25296 Cov.: 32 AF XY: 0.541 AC XY: 40183 AN XY: 74338

African (AFR) AF: 0.843 AC: 34983 AN: 41496

American (AMR) AF: 0.567 AC: 8670 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.405 AC: 1404 AN: 3468

East Asian (EAS) AF: 0.581 AC: 3008 AN: 5180

South Asian (SAS) AF: 0.337 AC: 1625 AN: 4820

European-Finnish (FIN) AF: 0.471 AC: 4974 AN: 10552

Middle Eastern (MID) AF: 0.486 AC: 143 AN: 294

European-Non Finnish (NFE) AF: 0.380 AC: 25831 AN: 67974

Other (OTH) AF: 0.491 AC: 1037 AN: 2114

Alfa AF: 0.415 Hom.: 7621

Bravo AF: 0.562

Asia WGS AF: 0.535 AC: 1859 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

- -

Nov 20, 2019

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	-0.84
CADD	Benign	3.9
DANN	Benign	0.67
PhyloP100		0.088
PromoterAI		0.077	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: rs1570474; hg19: chr9-676820; COSMIC: COSV63210967;