rs3824420

Positions:

• chr9-712766-G-A
• chr9-712766-G-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_015158.5(KANK1):​c.2000G>A​(p.Arg667His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0128 in 1,613,676 control chromosomes in the GnomAD database, including 1,241 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.027 (201 hom., cov: 32)
  • Exomes 𝑓: 0.011 (1040 hom.)
• Consequence: KANK1 NM_015158.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -1.70

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0020582974).
• BP6: Variant 9-712766-G-A is Benign according to our data. Variant chr9-712766-G-A is described in ClinVar as [Benign]. Clinvar id is 1166350.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.187 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KANK1	NM_015158.5	c.2000G>A	p.Arg667His	missense_variant	3/12	ENST00000382297.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KANK1	ENST00000382297.7	c.2000G>A	p.Arg667His	missense_variant	3/12	1	NM_015158.5	P2

Frequencies

GnomAD3 genomes AF: 0.0269 AC: 4088 AN: 152096 Hom.: 199 Cov.: 32

Gnomad AFR AF: 0.0309

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0821

Gnomad ASJ AF: 0.00317

Gnomad EAS AF: 0.197

Gnomad SAS AF: 0.0126

Gnomad FIN AF: 0.0297

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00137

Gnomad OTH AF: 0.0248

GnomAD3 exomes AF: 0.0380 AC: 9513 AN: 250034 Hom.: 677 AF XY: 0.0324 AC XY: 4381 AN XY: 135222

Gnomad AFR exome AF: 0.0325

Gnomad AMR exome AF: 0.123

Gnomad ASJ exome AF: 0.00279

Gnomad EAS exome AF: 0.196

Gnomad SAS exome AF: 0.00964

Gnomad FIN exome AF: 0.0262

Gnomad NFE exome AF: 0.00133

Gnomad OTH exome AF: 0.0257

GnomAD4 exome AF: 0.0113 AC: 16569 AN: 1461462 Hom.: 1040 Cov.: 34 AF XY: 0.0105 AC XY: 7633 AN XY: 726994

Gnomad4 AFR exome AF: 0.0289

Gnomad4 AMR exome AF: 0.118

Gnomad4 ASJ exome AF: 0.00226

Gnomad4 EAS exome AF: 0.151

Gnomad4 SAS exome AF: 0.00860

Gnomad4 FIN exome AF: 0.0259

Gnomad4 NFE exome AF: 0.000734

Gnomad4 OTH exome AF: 0.0222

GnomAD4 genome AF: 0.0269 AC: 4088 AN: 152214 Hom.: 201 Cov.: 32 AF XY: 0.0303 AC XY: 2251 AN XY: 74402

Gnomad4 AFR AF: 0.0308

Gnomad4 AMR AF: 0.0825

Gnomad4 ASJ AF: 0.00317

Gnomad4 EAS AF: 0.197

Gnomad4 SAS AF: 0.0122

Gnomad4 FIN AF: 0.0297

Gnomad4 NFE AF: 0.00137

Gnomad4 OTH AF: 0.0241

Alfa AF: 0.0105 Hom.: 201

Bravo AF: 0.0333

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.0331 AC: 146

ESP6500EA AF: 0.00116 AC: 10

ExAC AF: 0.0323 AC: 3919

Asia WGS AF: 0.106 AC: 369 AN: 3478

EpiCase AF: 0.000709

EpiControl AF: 0.00101

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 05, 2019	This variant is associated with the following publications: (PMID: 23263489) -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 30, 2024	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.065
BayesDel_addAF	Benign	-0.70	T
BayesDel_noAF	Benign	-0.64
CADD	Benign	0.0030
DANN	Benign	0.88
DEOGEN2	Benign	0.0096	T;T;T;.
Eigen	Benign	-1.8
Eigen_PC	Benign	-1.9
FATHMM_MKL	Benign	0.075	N
LIST_S2	Benign	0.70	.;T;.;T
MetaRNN	Benign	0.0021	T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	-0.43	N;N;N;.
MutationTaster	Benign	1.0	P;P;P;P
PrimateAI	Benign	0.17	T
PROVEAN	Benign	-0.16	N;.;N;N
REVEL	Benign	0.17
Sift	Benign	0.43	T;.;T;T
Sift4G	Benign	0.13	T;T;T;T
Polyphen		0.0010	B;B;B;.
Vest4		0.039
ClinPred		0.0055	T
GERP RS		-12
Varity_R		0.015
gMVP		0.26

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

Publications

LitVar

Other links and lift over

dbSNP: rs3824420; hg19: chr9-712766; COSMIC: COSV63213927;