Variant 1-14599217-G-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_201628.3(KAZN):c.220G>T(p.Ala74Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000265 in 1,393,734 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000085 ( 1 hom., cov: 32)

Exomes 𝑓: 0.000019 ( 1 hom. )

Consequence

KAZN
NM_201628.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.50

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.083028495).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KAZN	NM_201628.3 link	c.220G>T	p.Ala74Ser	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.220G>T	p.Ala74Ser	missense_variant	1/15	5	NM_201628.3	ENSP00000365198.2	Q674X7-1
KAZN	ENST00000503743.5 link	c.220G>T	p.Ala74Ser	missense_variant	2/9	1		ENSP00000426015.1	Q674X7-2
KAZN	ENST00000636203.1 link	c.484G>T	p.Ala162Ser	missense_variant	3/17	5		ENSP00000490958.1	A0A1B0GWK2
KAZN	ENST00000491547.1 link	n.514G>T		non_coding_transcript_exon_variant	1/7	2

Frequencies

GnomAD3 genomes

AF:

0.0000526

AC:

AN:

151982

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000393

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:

0.0000147

Gnomad OTH

AF:

0.000479

GnomAD4 exome

AF:

0.0000193

AC:

AN:

1241634

Hom.:

Cov.:

AF XY:

0.0000197

AC XY:

AN XY:

608198

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000342

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000297

Gnomad4 OTH exome

AF:

0.000398

GnomAD4 genome

AF:

0.0000855

AC:

AN:

152100

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74344

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.000392

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00285

Bravo

AF:

0.0000378

Asia WGS

AF:

0.0190

AC:

AN:

3478

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 01, 2024

The c.220G>T (p.A74S) alteration is located in exon 1 (coding exon 1) of the KAZN gene. This alteration results from a G to T substitution at nucleotide position 220, causing the alanine (A) at amino acid position 74 to be replaced by a serine (S). 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

Benign

0.070

BayesDel_addAF

Benign

-0.25

BayesDel_noAF

Benign

-0.60

CADD

Benign

DANN

Benign

0.94

DEOGEN2

Benign

0.0062

.;T;.

Eigen

Benign

-0.48

Eigen_PC

Benign

-0.27

FATHMM_MKL

Uncertain

0.84

LIST_S2

Benign

0.32

T;T;T

M_CAP

Uncertain

0.14

MetaRNN

Benign

0.083

T;T;T

MetaSVM

Benign

-0.94

MutationAssessor

Benign

0.0

.;N;N

PrimateAI

Uncertain

0.74

PROVEAN

Benign

0.17

.;N;N

REVEL

Benign

0.12

Sift

Benign

0.42

.;T;T

Sift4G

Benign

0.67

.;T;T

Polyphen

0.23, 0.021

.;B;B

Vest4

0.12, 0.22

MutPred

0.12

.;Gain of relative solvent accessibility (P = 0.2629);Gain of relative solvent accessibility (P = 0.2629);

MVP

0.38

MPC

0.63

ClinPred

0.064

GERP RS

3.8

Varity_R

0.071

gMVP

0.093

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over