Genetic Variant NM_015158.5:c.3554-13_3554-5delTTTTTTTTT (chr9-740769-CTTTTTTTTT-C) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_015158.5(KANK1):c.3554-13_3554-5delTTTTTTTTT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000294 in 1,361,096 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.0 ( 0 hom., cov: 0)

Exomes 𝑓: 0.0000029 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

KANK1
NM_015158.5 splice_region, intron

Scores

Not classified

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 3.56

Publications

0 publications found

Variant links:

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

KANK1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KANK1	NM_015158.5 link	c.3554-13_3554-5delTTTTTTTTT		splice_region_variant, intron_variant	Intron 8 of 11	ENST00000382297.7	NP_055973.2	Q14678-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KANK1	ENST00000382297.7 link	c.3554-22_3554-14delTTTTTTTTT		intron_variant	Intron 8 of 11	1	NM_015158.5	ENSP00000371734.2		Q14678-1

Frequencies

GnomAD3 genomes

AF:

0.00

AC:

AN:

144720

Hom.:

Cov.:

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00000294

AC:

AN:

1361096

Hom.:

AF XY:

0.00000296

AC XY:

AN XY:

676636

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.0000334

AC:

AN:

29958

American (AMR)

AF:

0.00

AC:

AN:

33724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

23402

East Asian (EAS)

AF:

0.00

AC:

AN:

37944

South Asian (SAS)

AF:

0.00

AC:

AN:

76896

European-Finnish (FIN)

AF:

0.00

AC:

AN:

46384

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5380

European-Non Finnish (NFE)

AF:

0.00000190

AC:

AN:

1051290

Other (OTH)

AF:

0.0000178

AC:

AN:

56118

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.0000469829), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.313

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

144720

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

70046

African (AFR)

AF:

0.00

AC:

AN:

39652

American (AMR)

AF:

0.00

AC:

AN:

14246

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3310

East Asian (EAS)

AF:

0.00

AC:

AN:

4822

South Asian (SAS)

AF:

0.00

AC:

AN:

4600

European-Finnish (FIN)

AF:

0.00

AC:

AN:

9134

Middle Eastern (MID)

AF:

0.00

AC:

AN:

300

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

65784

Other (OTH)

AF:

0.00

AC:

AN:

1994

Alfa

AF:

0.00

Hom.:

333

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

3.6

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over