Variant 1-14599073-C-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4

The NM_201628.3(KAZN):c.76C>A(p.Leu26Met) variant causes a missense change. The variant allele was found at a frequency of 0.00000071 in 1,409,410 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 7.1e-7 ( 0 hom. )

Consequence

KAZN
NM_201628.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.53

Variant links:

Genes affected

KAZN (HGNC:29173): (kazrin, periplakin interacting protein) This gene encodes a protein that plays a role in desmosome assembly, cell adhesion, cytoskeletal organization, and epidermal differentiation. This protein co-localizes with desmoplakin and the cytolinker protein periplakin. In general, this protein localizes to the nucleus, desmosomes, cell membrane, and cortical actin-based structures. Some isoforms of this protein also associate with microtubules. Alternative splicing results in multiple transcript variants encoding distinct isoforms. Additional splice variants have been described but their biological validity has not been verified. [provided by RefSeq, Aug 2011]

KAZN links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.36897004).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KAZN	NM_201628.3 link	c.76C>A	p.Leu26Met	missense_variant	1/15	ENST00000376030.7	NP_963922.2	Q674X7-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
KAZN	ENST00000376030.7 link	c.76C>A	p.Leu26Met	missense_variant	1/15	5	NM_201628.3	ENSP00000365198.2	Q674X7-1
KAZN	ENST00000503743.5 link	c.76C>A	p.Leu26Met	missense_variant	2/9	1		ENSP00000426015.1	Q674X7-2
KAZN	ENST00000636203.1 link	c.340C>A	p.Leu114Met	missense_variant	3/17	5		ENSP00000490958.1	A0A1B0GWK2
KAZN	ENST00000491547.1 link	n.370C>A		non_coding_transcript_exon_variant	1/7	2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

7.10e-7

AC:

AN:

1409410

Hom.:

Cov.:

AF XY:

0.00000143

AC XY:

AN XY:

700978

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

9.17e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 09, 2024

The c.76C>A (p.L26M) alteration is located in exon 1 (coding exon 1) of the KAZN gene. This alteration results from a C to A substitution at nucleotide position 76, causing the leucine (L) at amino acid position 26 to be replaced by a methionine (M). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.93

BayesDel_addAF

Benign

-0.078

BayesDel_noAF

Benign

-0.35

CADD

Pathogenic

DANN

Uncertain

0.99

DEOGEN2

Benign

0.014

.;T;.

Eigen

Uncertain

0.50

Eigen_PC

Uncertain

0.45

FATHMM_MKL

Uncertain

0.90

LIST_S2

Uncertain

0.89

D;D;D

M_CAP

Pathogenic

0.64

MetaRNN

Benign

0.37

T;T;T

MetaSVM

Benign

-0.66

MutationAssessor

Benign

1.1

.;L;L

PrimateAI

Pathogenic

0.94

PROVEAN

Benign

-0.090

.;N;N

REVEL

Benign

0.24

Sift

Benign

0.040

.;D;D

Sift4G

Benign

0.16

.;T;T

Polyphen

0.99, 1.0

.;D;D

Vest4

0.34, 0.46

MutPred

0.38

.;Gain of catalytic residue at L26 (P = 0.028);Gain of catalytic residue at L26 (P = 0.028);

MVP

0.62

MPC

1.5

ClinPred

0.88

GERP RS

3.8

Varity_R

0.10

gMVP

0.24

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

No publications associated with this variant yet.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over