1-14599215-G-C

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_201628.3(KAZN):c.218G>C(p.Gly73Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000032 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: KAZN NM_201628.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.65

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]

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.061060935).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KAZN	NM_201628.3	c.218G>C	p.Gly73Ala	missense_variant	1/15	ENST00000376030.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KAZN	ENST00000376030.7	c.218G>C	p.Gly73Ala	missense_variant	1/15	5	NM_201628.3	P2
KAZN	ENST00000503743.5	c.218G>C	p.Gly73Ala	missense_variant	2/9	1
KAZN	ENST00000636203.1	c.482G>C	p.Gly161Ala	missense_variant	3/17	5		A2
KAZN	ENST00000491547.1	n.512G>C		non_coding_transcript_exon_variant	1/7	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000321 AC: 4 AN: 1246582 Hom.: 0 Cov.: 32 AF XY: 0.00000164 AC XY: 1 AN XY: 610904

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: 0.0000236

Gnomad4 NFE exome AF: 0.00000297

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ExAC AF: 0.00000938 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 01, 2022

The c.218G>C (p.G73A) alteration is located in exon 1 (coding exon 1) of the KAZN gene. This alteration results from a G to C substitution at nucleotide position 218, causing the glycine (G) at amino acid position 73 to be replaced by an alanine (A). 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	0.075
BayesDel_addAF	Benign	-0.30	T
BayesDel_noAF	Benign	-0.67
Cadd	Benign	20
Dann	Benign	0.80
Eigen	Benign	-0.57
Eigen_PC	Benign	-0.40
FATHMM_MKL	Benign	0.70	D
LIST_S2	Benign	0.45	T;T;T
M_CAP	Benign	0.048	D
MetaRNN	Benign	0.061	T;T;T
MetaSVM	Benign	-0.89	T
MutationTaster	Benign	0.98	N;N;N
PrimateAI	Uncertain	0.73	T
Polyphen		0.0030, 0.0050	.;B;B
Vest4		0.11, 0.13
MutPred		0.083		.;Gain of MoRF binding (P = 0.2819);Gain of MoRF binding (P = 0.2819);
MVP		0.26
MPC		0.74
ClinPred		0.068	T
GERP RS		2.7
Varity_R		0.060
gMVP		0.14

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

Other links and lift over

dbSNP: rs753797722; hg19: chr1-14925711;