Genetic Variant NM_015158.5:c.3554-6_3554-5dupTT (chr9-740769-C-CTT) – ACMG Classification: Benign (-8 pts)

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BS1BS2

The NM_015158.5(KANK1):c.3554-6_3554-5dupTT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.014 ( 49 hom., cov: 0)

Exomes 𝑓: 0.0015 ( 0 hom. )

Consequence

KANK1
NM_015158.5 splice_region, intron

Scores

Not classified

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.110

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: Benign. The variant received -8 ACMG points.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0145 (2097/144728) while in subpopulation AFR AF = 0.0492 (1952/39700). AF 95% confidence interval is 0.0474. There are 49 homozygotes in GnomAd4. There are 968 alleles in the male GnomAd4 subpopulation. Median coverage is 0. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 49 Unknown,AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KANK1	NM_015158.5 link	c.3554-6_3554-5dupTT		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.3554-23_3554-22insTT		intron_variant	Intron 8 of 11	1	NM_015158.5	ENSP00000371734.2		Q14678-1

Frequencies

GnomAD3 genomes

AF:

0.0145

AC:

2094

AN:

144682

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0492

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00660

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00124

Gnomad SAS

AF:

0.000870

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000167

Gnomad OTH

AF:

0.0150

GnomAD4 exome

AF:

0.00146

AC:

1979

AN:

1358260

Hom.:

Cov.:

AF XY:

0.00135

AC XY:

912

AN XY:

675220

show subpopulations

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

African (AFR)

AF:

0.0289

AC:

851

AN:

29480

American (AMR)

AF:

0.00381

AC:

128

AN:

33622

Ashkenazi Jewish (ASJ)

AF:

0.00141

AC:

AN:

23360

East Asian (EAS)

AF:

0.00296

AC:

112

AN:

37822

South Asian (SAS)

AF:

0.00169

AC:

130

AN:

76732

European-Finnish (FIN)

AF:

0.00164

AC:

AN:

46310

Middle Eastern (MID)

AF:

0.00112

AC:

AN:

5368

European-Non Finnish (NFE)

AF:

0.000485

AC:

509

AN:

1049604

Other (OTH)

AF:

0.00239

AC:

134

AN:

55962

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.302

Heterozygous variant carriers

151

302

452

603

754

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

144

192

240

<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

AF:

0.0145

AC:

2097

AN:

144728

Hom.:

Cov.:

AF XY:

0.0138

AC XY:

968

AN XY:

70104

show subpopulations

African (AFR)

AF:

0.0492

AC:

1952

AN:

39700

American (AMR)

AF:

0.00659

AC:

AN:

14256

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3310

East Asian (EAS)

AF:

0.00125

AC:

AN:

4810

South Asian (SAS)

AF:

0.000872

AC:

AN:

4588

European-Finnish (FIN)

AF:

0.00

AC:

AN:

9134

Middle Eastern (MID)

AF:

0.00

AC:

AN:

276

European-Non Finnish (NFE)

AF:

0.000167

AC:

AN:

65772

Other (OTH)

AF:

0.0150

AC:

AN:

2004

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.484

Heterozygous variant carriers

175

263

350

438

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

110

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00

Hom.:

333

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

0.11

Mutation Taster

=100/0

polymorphism

(source)

Splicing

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over