ENST00000382293.7:c.-326A>T

Variant names:

• chr9-710915-A-T
• rs61737971
• ENST00000382293.7:c.-326A>T

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The ENST00000382293.7(KANK1):​c.-326A>T variant causes a 5 prime UTR premature start codon gain change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00859 in 1,614,174 control chromosomes in the GnomAD database, including 82 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0060 (6 hom., cov: 32)
  • Exomes 𝑓: 0.0089 (76 hom.)
• Consequence: KANK1 ENST00000382293.7 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts U:1 B:6
• Conservation: PhyloP100: 8.84
• Publications: 9 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

ACMG classification

Our verdict: Benign. The variant received -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.012142837).
• BP6: Variant 9-710915-A-T is Benign according to our data. Variant chr9-710915-A-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 377350.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Homozygotes in GnomAd4 at 6 Unknown,AD,AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000382293.7. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KANK1	NM_015158.5	MANE Select	c.149A>T	p.Asp50Val	missense	Exon 3 of 12	NP_055973.2	Q14678-1
	KANK1	NM_001354333.2		c.-326A>T		5_prime_UTR_premature_start_codon_gain	Exon 3 of 12	NP_001341262.1	Q14678-2
	KANK1	NM_001354335.2		c.-326A>T		5_prime_UTR_premature_start_codon_gain	Exon 2 of 11	NP_001341264.1	Q14678-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KANK1	ENST00000382293.7	TSL:1	c.-326A>T		5_prime_UTR_premature_start_codon_gain	Exon 2 of 11	ENSP00000371730.3	Q14678-2
	KANK1	ENST00000382297.7	TSL:1 MANE Select	c.149A>T	p.Asp50Val	missense	Exon 3 of 12	ENSP00000371734.2	Q14678-1
	KANK1	ENST00000382303.5	TSL:1	c.149A>T	p.Asp50Val	missense	Exon 7 of 16	ENSP00000371740.1	Q14678-1

Frequencies

GnomAD3 genomes AF: 0.00597 AC: 908 AN: 152184 Hom.: 6 Cov.: 32

Gnomad AFR AF: 0.00193

Gnomad AMI AF: 0.0789

Gnomad AMR AF: 0.00301

Gnomad ASJ AF: 0.00288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00165

Gnomad FIN AF: 0.00245

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00969

Gnomad OTH AF: 0.00335

GnomAD2 exomes AF: 0.00565 AC: 1420 AN: 251486 AF XY: 0.00561

Gnomad AFR exome AF: 0.00166

Gnomad AMR exome AF: 0.00301

Gnomad ASJ exome AF: 0.00198

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00273

Gnomad NFE exome AF: 0.00993

Gnomad OTH exome AF: 0.00668

GnomAD4 exome AF: 0.00887 AC: 12960 AN: 1461872 Hom.: 76 Cov.: 33 AF XY: 0.00854 AC XY: 6208 AN XY: 727234

African (AFR) AF: 0.00131 AC: 44 AN: 33480

American (AMR) AF: 0.00309 AC: 138 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00279 AC: 73 AN: 26136

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39700

South Asian (SAS) AF: 0.00191 AC: 165 AN: 86258

European-Finnish (FIN) AF: 0.00358 AC: 191 AN: 53418

Middle Eastern (MID) AF: 0.00104 AC: 6 AN: 5768

European-Non Finnish (NFE) AF: 0.0107 AC: 11855 AN: 1111992

Other (OTH) AF: 0.00806 AC: 487 AN: 60396

GnomAD4 genome AF: 0.00596 AC: 907 AN: 152302 Hom.: 6 Cov.: 32 AF XY: 0.00507 AC XY: 378 AN XY: 74486

African (AFR) AF: 0.00193 AC: 80 AN: 41558

American (AMR) AF: 0.00301 AC: 46 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.00288 AC: 10 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.00166 AC: 8 AN: 4832

European-Finnish (FIN) AF: 0.00245 AC: 26 AN: 10616

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00967 AC: 658 AN: 68026

Other (OTH) AF: 0.00331 AC: 7 AN: 2114

Alfa AF: 0.00709 Hom.: 6

Bravo AF: 0.00634

TwinsUK AF: 0.00809 AC: 30

ALSPAC AF: 0.0112 AC: 43

ESP6500AA AF: 0.00295 AC: 13

ESP6500EA AF: 0.00977 AC: 84

ExAC AF: 0.00607 AC: 737

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.00878

EpiControl AF: 0.00723

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not provided (5)
-	1	-	Amyotrophic lateral sclerosis (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.56
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Uncertain	0.060
CADD	Pathogenic	27
DANN	Uncertain	0.99
DEOGEN2	Benign	0.39	T
Eigen	Pathogenic	0.80
Eigen_PC	Pathogenic	0.82
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Benign	0.053	D
MetaRNN	Benign	0.012	T
MetaSVM	Benign	-0.50	T
MutationAssessor	Benign	2.0	M
PhyloP100		8.8
PrimateAI	Uncertain	0.71	T
PROVEAN	Pathogenic	-6.6	D
REVEL	Uncertain	0.54
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.0020	D
Polyphen		0.99	D
Vest4		0.77
MVP		0.71
ClinPred		0.027	T
GERP RS		6.0
Varity_R		0.94
gMVP		0.34
Mutation Taster		=284/16	polymorphism

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: rs61737971; hg19: chr9-710915; COSMIC: COSV63212695;