NM_201628.3:c.2180T>C

Variant summary

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

The NM_201628.3(KAZN):​c.2180T>C​(p.Ile727Thr) variant causes a missense change. The variant allele was found at a frequency of 0.00000621 in 1,611,336 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: 𝑓 0.0000066 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0000062 ( 0 hom. )

Consequence

KAZN
NM_201628.3 missense

Scores

4
15

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.93
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]
TMEM51-AS1 (HGNC:26301): (TMEM51 antisense RNA 1)

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=0.16064337).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
KAZNNM_201628.3 linkc.2180T>C p.Ile727Thr missense_variant Exon 15 of 15 ENST00000376030.7 NP_963922.2 Q674X7-1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
KAZNENST00000376030.7 linkc.2180T>C p.Ile727Thr missense_variant Exon 15 of 15 5 NM_201628.3 ENSP00000365198.2 Q674X7-1
TMEM51-AS1ENST00000404665.4 linkn.4301A>G non_coding_transcript_exon_variant Exon 5 of 5 1
KAZNENST00000636203.1 linkc.2444T>C p.Ile815Thr missense_variant Exon 17 of 17 5 ENSP00000490958.1 A0A1B0GWK2
TMEM51-AS1ENST00000310916.6 linkn.4428A>G non_coding_transcript_exon_variant Exon 6 of 6 2

Frequencies

GnomAD3 genomes
AF:
0.00000657
AC:
1
AN:
152150
Hom.:
0
Cov.:
32
show subpopulations
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:
0.000478
GnomAD3 exomes
AF:
0.00000810
AC:
2
AN:
246968
Hom.:
0
AF XY:
0.00000751
AC XY:
1
AN XY:
133218
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.0000551
Gnomad SAS exome
AF:
0.0000337
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000617
AC:
9
AN:
1459186
Hom.:
0
Cov.:
30
AF XY:
0.00000551
AC XY:
4
AN XY:
725544
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.0000252
Gnomad4 SAS exome
AF:
0.0000117
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000630
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.00000657
AC:
1
AN:
152150
Hom.:
0
Cov.:
32
AF XY:
0.00
AC XY:
0
AN XY:
74326
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.000478

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Sep 18, 2024
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.2180T>C (p.I727T) alteration is located in exon 15 (coding exon 15) of the KAZN gene. This alteration results from a T to C substitution at nucleotide position 2180, causing the isoleucine (I) at amino acid position 727 to be replaced by a threonine (T). 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
0.099
BayesDel_addAF
Benign
-0.16
T
BayesDel_noAF
Benign
-0.30
CADD
Benign
21
DANN
Uncertain
0.99
DEOGEN2
Benign
0.0058
.;T
Eigen
Benign
-0.073
Eigen_PC
Benign
0.13
FATHMM_MKL
Uncertain
0.86
D
LIST_S2
Benign
0.78
T;T
M_CAP
Benign
0.0055
T
MetaRNN
Benign
0.16
T;T
MetaSVM
Benign
-1.1
T
MutationAssessor
Uncertain
2.1
.;M
PrimateAI
Uncertain
0.76
T
PROVEAN
Benign
-0.52
.;N
REVEL
Benign
0.10
Sift
Benign
0.17
.;T
Sift4G
Benign
0.081
.;T
Polyphen
0.079
.;B
Vest4
0.52
MutPred
0.24
.;Loss of stability (P = 0.0107);
MVP
0.24
MPC
0.48
ClinPred
0.62
D
GERP RS
5.4
Varity_R
0.063
gMVP
0.33

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.

Other links and lift over

dbSNP: rs1390420181; hg19: chr1-15440983; API