chr1-14599136-G-C

Variant names:

• chr1-14599136-G-C
• rs775963111
• NM_201628.3:c.139G>C

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_201628.3(KAZN):​c.139G>C​(p.Gly47Arg) variant causes a missense change. The variant allele was found at a frequency of 0.000000767 in 1,303,314 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: 7.7e-7 (0 hom.)
• Consequence: KAZN NM_201628.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.88
• Publications: 0 publications found

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

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.17518726).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_201628.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KAZN	NM_201628.3	MANE Select	c.139G>C	p.Gly47Arg	missense	Exon 1 of 15	NP_963922.2	Q674X7-1
	KAZN	NM_001437721.1		c.139G>C	p.Gly47Arg	missense	Exon 2 of 9	NP_001424650.1
	KAZN	NM_015209.3		c.139G>C	p.Gly47Arg	missense	Exon 1 of 8	NP_056024.1	Q674X7-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KAZN	ENST00000376030.7	TSL:5 MANE Select	c.139G>C	p.Gly47Arg	missense	Exon 1 of 15	ENSP00000365198.2	Q674X7-1
	KAZN	ENST00000503743.5	TSL:1	c.139G>C	p.Gly47Arg	missense	Exon 2 of 9	ENSP00000426015.1	Q674X7-2
	KAZN	ENST00000636203.1	TSL:5	c.403G>C	p.Gly135Arg	missense	Exon 3 of 17	ENSP00000490958.1	A0A1B0GWK2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000866 AC: 1 AN: 115478 AF XY: 0.0000149

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000108

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 7.67e-7 AC: 1 AN: 1303314 Hom.: 0 Cov.: 33 AF XY: 0.00000155 AC XY: 1 AN XY: 643962

African (AFR) AF: 0.00 AC: 0 AN: 25844

American (AMR) AF: 0.0000543 AC: 1 AN: 18432

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 20884

East Asian (EAS) AF: 0.00 AC: 0 AN: 30778

South Asian (SAS) AF: 0.00 AC: 0 AN: 61194

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 46950

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4762

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1041528

Other (OTH) AF: 0.00 AC: 0 AN: 52942

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ExAC AF: 0.00000897 AC: 1

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.30
BayesDel_addAF	Benign	-0.14	T
BayesDel_noAF	Benign	-0.44
CADD	Uncertain	24
DANN	Uncertain	0.98
DEOGEN2	Benign	0.0064	T
Eigen	Benign	0.060
Eigen_PC	Benign	0.071
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Benign	0.43	T
M_CAP	Uncertain	0.14	D
MetaRNN	Benign	0.18	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.34	N
PhyloP100		4.9
PrimateAI	Pathogenic	0.91	D
PROVEAN	Benign	-0.11	N
REVEL	Benign	0.075
Sift	Uncertain	0.029	D
Sift4G	Benign	0.15	T
Polyphen		0.82	P
Vest4		0.21
MutPred		0.26		Gain of methylation at G47 (P = 0.0184)
MVP		0.22
MPC		1.9
ClinPred		0.41	T
GERP RS		2.5
PromoterAI		-0.057	Neutral
Varity_R		0.083
gMVP		0.095
Mutation Taster		=85/15	polymorphism

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

Other links and lift over

dbSNP: rs775963111; hg19: chr1-14925632;