NM_201628.3:c.220G>T

Variant names:

• chr1-14599217-G-T
• rs1031734291
• NM_201628.3:c.220G>T

Variant summary

Our verdict is Likely benign. The variant received -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. 14/22 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
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.50
• 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: Likely_benign. The variant received -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.083028495).

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.220G>T	p.Ala74Ser	missense	Exon 1 of 15	NP_963922.2	Q674X7-1
	KAZN	NM_001437721.1		c.220G>T	p.Ala74Ser	missense	Exon 2 of 9	NP_001424650.1
	KAZN	NM_015209.3		c.220G>T	p.Ala74Ser	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.220G>T	p.Ala74Ser	missense	Exon 1 of 15	ENSP00000365198.2	Q674X7-1
	KAZN	ENST00000503743.5	TSL:1	c.220G>T	p.Ala74Ser	missense	Exon 2 of 9	ENSP00000426015.1	Q674X7-2
	KAZN	ENST00000636203.1	TSL:5	c.484G>T	p.Ala162Ser	missense	Exon 3 of 17	ENSP00000490958.1	A0A1B0GWK2

Frequencies

GnomAD3 genomes AF: 0.0000526 AC: 8 AN: 151982 Hom.: 0 Cov.: 32

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

GnomAD2 exomes AF: 0.0000438 AC: 3 AN: 68456 AF XY: 0.0000763

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000649

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000718

GnomAD4 exome AF: 0.0000193 AC: 24 AN: 1241634 Hom.: 1 Cov.: 32 AF XY: 0.0000197 AC XY: 12 AN XY: 608198

African (AFR) AF: 0.00 AC: 0 AN: 25186

American (AMR) AF: 0.00 AC: 0 AN: 14700

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 18586

East Asian (EAS) AF: 0.0000342 AC: 1 AN: 29272

South Asian (SAS) AF: 0.00 AC: 0 AN: 49018

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 42036

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3496

European-Non Finnish (NFE) AF: 0.00000297 AC: 3 AN: 1009066

Other (OTH) AF: 0.000398 AC: 20 AN: 50274

GnomAD4 genome AF: 0.0000855 AC: 13 AN: 152100 Hom.: 1 Cov.: 32 AF XY: 0.0000269 AC XY: 2 AN XY: 74344

African (AFR) AF: 0.00 AC: 0 AN: 41540

American (AMR) AF: 0.000392 AC: 6 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5106

South Asian (SAS) AF: 0.00 AC: 0 AN: 4820

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10596

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 67956

Other (OTH) AF: 0.00285 AC: 6 AN: 2108

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000378

Asia WGS AF: 0.0190 AC: 66 AN: 3478

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	0.070
BayesDel_addAF	Benign	-0.25	T
BayesDel_noAF	Benign	-0.60
CADD	Benign	19
DANN	Benign	0.94
DEOGEN2	Benign	0.0062	T
Eigen	Benign	-0.48
Eigen_PC	Benign	-0.27
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Benign	0.32	T
M_CAP	Uncertain	0.14	D
MetaRNN	Benign	0.083	T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	0.0	N
PhyloP100		3.5
PrimateAI	Uncertain	0.74	T
PROVEAN	Benign	0.17	N
REVEL	Benign	0.12
Sift	Benign	0.42	T
Sift4G	Benign	0.67	T
Polyphen		0.23	B
Vest4		0.12
MutPred		0.12		Gain of relative solvent accessibility (P = 0.2629)
MVP		0.38
MPC		0.63
ClinPred		0.064	T
GERP RS		3.8
Varity_R		0.071
gMVP		0.093
Mutation Taster		=96/4	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: rs1031734291; hg19: chr1-14925713;