1-15112540-G-A

Variant names:

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_201628.3(KAZN):c.2162G>A(p.Arg721Gln) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.0000739 in 1,556,294 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/23 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R721W) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000062 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000075 ( 0 hom. )

Consequence

KAZN
NM_201628.3 missense, splice_region

Scores

Splicing: ADA: 0.4505

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.87

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:

TMEM51-AS1 (HGNC:26301): (TMEM51 antisense RNA 1)

TMEM51-AS1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.22839895).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KAZN	NM_201628.3 link	c.2162G>A	p.Arg721Gln	missense_variant, splice_region_variant	Exon 14 of 15	ENST00000376030.7	NP_963922.2	Q674X7-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
KAZN	ENST00000376030.7 link	c.2162G>A	p.Arg721Gln	missense_variant, splice_region_variant	Exon 14 of 15	5	NM_201628.3	ENSP00000365198.2	Q674X7-1
TMEM51-AS1	ENST00000404665.4 link	n.6248C>T		non_coding_transcript_exon_variant	Exon 5 of 5	1
KAZN	ENST00000636203.1 link	c.2426G>A	p.Arg809Gln	missense_variant, splice_region_variant	Exon 16 of 17	5		ENSP00000490958.1	A0A1B0GWK2
TMEM51-AS1	ENST00000310916.6 link	n.6375C>T		non_coding_transcript_exon_variant	Exon 6 of 6	2

Frequencies

GnomAD3 genomes

AF:

0.0000619

AC:

AN:

129274

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000292

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000775

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:

0.000102

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000278

AC:

AN:

216040

Hom.:

AF XY:

0.00000859

AC XY:

AN XY:

116412

show subpopulations

Gnomad AFR exome

AF:

0.0000759

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000624

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000416

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000750

AC:

107

AN:

1427020

Hom.:

Cov.:

AF XY:

0.0000764

AC XY:

AN XY:

706678

show subpopulations

Gnomad4 AFR exome

AF:

0.0000612

Gnomad4 AMR exome

AF:

0.0000239

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000259

Gnomad4 SAS exome

AF:

0.0000122

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000890

Gnomad4 OTH exome

AF:

0.0000851

GnomAD4 genome

AF:

0.0000619

AC:

AN:

129274

Hom.:

Cov.:

AF XY:

0.0000634

AC XY:

AN XY:

63044

show subpopulations

Gnomad4 AFR

AF:

0.0000292

Gnomad4 AMR

AF:

0.0000775

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000102

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000965

Hom.:

Bravo

AF:

0.0000604

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.00000826

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Dec 12, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.2162G>A (p.R721Q) alteration is located in exon 14 (coding exon 14) of the KAZN gene. This alteration results from a G to A substitution at nucleotide position 2162, causing the arginine (R) at amino acid position 721 to be replaced by a glutamine (Q). 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

0.14

BayesDel_addAF

Benign

-0.26

BayesDel_noAF

Benign

-0.42

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.0061

.;T

Eigen

Uncertain

0.40

Eigen_PC

Uncertain

0.44

FATHMM_MKL

Benign

0.71

LIST_S2

Uncertain

0.87

D;D

M_CAP

Benign

0.011

MetaRNN

Benign

0.23

T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.5

.;L

PrimateAI

Benign

0.42

PROVEAN

Benign

0.040

.;N

REVEL

Benign

0.15

Sift

Uncertain

0.010

.;D

Sift4G

Benign

0.14

.;T

Polyphen

0.99

.;D

Vest4

0.44

MVP

0.40

MPC

0.12

ClinPred

0.18

GERP RS

5.6

Varity_R

0.14

gMVP

0.40

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.45

dbscSNV1_RF

Benign

0.38

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