9-676954-T-C

Variant names:

• chr9-676954-T-C
• rs2296055
• NM_015158.5:c.-19T>C

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.-19T>C variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.257 in 1,608,986 control chromosomes in the GnomAD database, including 64,360 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.37 (13419 hom., cov: 33)
  • Exomes 𝑓: 0.24 (50941 hom.)
• Consequence: KANK1 NM_015158.5 5_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.573
• Publications: 18 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 9-676954-T-C is Benign according to our data. Variant chr9-676954-T-C is described in ClinVar as [Benign]. Clinvar id is 1238818.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.641 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KANK1	NM_015158.5	c.-19T>C		5_prime_UTR_variant	Exon 2 of 12	ENST00000382297.7	NP_055973.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KANK1	ENST00000382297.7	c.-19T>C		5_prime_UTR_variant	Exon 2 of 12	1	NM_015158.5	ENSP00000371734.2

Frequencies

GnomAD3 genomes AF: 0.375 AC: 56933 AN: 151990 Hom.: 13386 Cov.: 33

Gnomad AFR AF: 0.648

Gnomad AMI AF: 0.214

Gnomad AMR AF: 0.385

Gnomad ASJ AF: 0.259

Gnomad EAS AF: 0.577

Gnomad SAS AF: 0.269

Gnomad FIN AF: 0.326

Gnomad MID AF: 0.348

Gnomad NFE AF: 0.215

Gnomad OTH AF: 0.328

GnomAD2 exomes AF: 0.310 AC: 77652 AN: 250636 AF XY: 0.295

Gnomad AFR exome AF: 0.657

Gnomad AMR exome AF: 0.380

Gnomad ASJ exome AF: 0.258

Gnomad EAS exome AF: 0.574

Gnomad FIN exome AF: 0.311

Gnomad NFE exome AF: 0.217

Gnomad OTH exome AF: 0.286

GnomAD4 exome AF: 0.245 AC: 356813 AN: 1456876 Hom.: 50941 Cov.: 30 AF XY: 0.244 AC XY: 176536 AN XY: 724942

African (AFR) AF: 0.669 AC: 22245 AN: 33268

American (AMR) AF: 0.384 AC: 17107 AN: 44602

Ashkenazi Jewish (ASJ) AF: 0.255 AC: 6654 AN: 26106

East Asian (EAS) AF: 0.565 AC: 22389 AN: 39612

South Asian (SAS) AF: 0.251 AC: 21574 AN: 85940

European-Finnish (FIN) AF: 0.309 AC: 16500 AN: 53394

Middle Eastern (MID) AF: 0.272 AC: 1565 AN: 5756

European-Non Finnish (NFE) AF: 0.210 AC: 232195 AN: 1108006

Other (OTH) AF: 0.276 AC: 16584 AN: 60192

GnomAD4 genome AF: 0.375 AC: 57006 AN: 152110 Hom.: 13419 Cov.: 33 AF XY: 0.379 AC XY: 28215 AN XY: 74360

African (AFR) AF: 0.648 AC: 26851 AN: 41458

American (AMR) AF: 0.386 AC: 5894 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.259 AC: 900 AN: 3470

East Asian (EAS) AF: 0.576 AC: 2982 AN: 5174

South Asian (SAS) AF: 0.269 AC: 1297 AN: 4820

European-Finnish (FIN) AF: 0.326 AC: 3449 AN: 10586

Middle Eastern (MID) AF: 0.344 AC: 101 AN: 294

European-Non Finnish (NFE) AF: 0.215 AC: 14630 AN: 67994

Other (OTH) AF: 0.334 AC: 707 AN: 2114

Alfa AF: 0.283 Hom.: 11694

Bravo AF: 0.392

Asia WGS AF: 0.481 AC: 1669 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

- -

Dec 25, 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	8.2
DANN	Benign	0.56
PhyloP100		0.57
PromoterAI		-0.011	Neutral
Mutation Taster		=300/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs2296055; hg19: chr9-676954; COSMIC: COSV63210971;