1-14960756-C-T

Variant names:

• chr1-14960756-C-T
• rs763136249
• NM_201628.3:c.299C>T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_201628.3(KAZN):​c.299C>T​(p.Ala100Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000138 in 1,448,858 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 0.0 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000014 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: KAZN NM_201628.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.93
• Publications: 4 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.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.05955884).

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.299C>T	p.Ala100Val	missense	Exon 2 of 15	NP_963922.2	Q674X7-1
	KAZN	NM_001437721.1		c.299C>T	p.Ala100Val	missense	Exon 3 of 9	NP_001424650.1
	KAZN	NM_015209.3		c.299C>T	p.Ala100Val	missense	Exon 2 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.299C>T	p.Ala100Val	missense	Exon 2 of 15	ENSP00000365198.2	Q674X7-1
	KAZN	ENST00000503743.5	TSL:1	c.299C>T	p.Ala100Val	missense	Exon 3 of 9	ENSP00000426015.1	Q674X7-2
	KAZN	ENST00000361144.9	TSL:1	c.281C>T	p.Ala94Val	missense	Exon 2 of 8	ENSP00000354727.5	Q674X7-3

Frequencies

GnomAD3 genomes AF: 0.00 AC: 0 AN: 152212 Hom.: 0 Cov.: 33

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: 0.00

GnomAD2 exomes AF: 0.0000176 AC: 4 AN: 227272 AF XY: 0.0000163

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000124

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: 0.0000138 AC: 20 AN: 1448858 Hom.: 0 Cov.: 31 AF XY: 0.0000111 AC XY: 8 AN XY: 719210

African (AFR) AF: 0.00 AC: 0 AN: 33328

American (AMR) AF: 0.0000935 AC: 4 AN: 42802

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25740

East Asian (EAS) AF: 0.0000255 AC: 1 AN: 39284

South Asian (SAS) AF: 0.0000357 AC: 3 AN: 83950

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52280

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5752

European-Non Finnish (NFE) AF: 0.0000109 AC: 12 AN: 1105808

Other (OTH) AF: 0.00 AC: 0 AN: 59914

GnomAD4 genome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 152330 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 74478

African (AFR) AF: 0.00 AC: 0 AN: 41566

American (AMR) AF: 0.00 AC: 0 AN: 15306

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68032

Other (OTH) AF: 0.00 AC: 0 AN: 2114

Alfa AF: 0.0000434 Hom.: 0

Bravo AF: 0.00000756

ExAC AF: 0.0000165 AC: 2

Asia WGS AF: 0.000289 AC: 1 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	0.11
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Benign	-0.50
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.021	T
Eigen	Benign	-0.28
Eigen_PC	Benign	-0.15
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Uncertain	0.97	D
M_CAP	Benign	0.018	T
MetaRNN	Benign	0.060	T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	0.69	N
PhyloP100		1.9
PrimateAI	Benign	0.28	T
PROVEAN	Benign	-0.91	N
REVEL	Benign	0.012
Sift	Benign	0.063	T
Sift4G	Benign	0.20	T
Polyphen		0.031	B
Vest4		0.33
MutPred		0.13		Gain of methylation at K101 (P = 0.0346)
MVP		0.48
MPC		0.68
ClinPred		0.14	T
GERP RS		3.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.065
gMVP		0.18
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: rs763136249; hg19: chr1-15287252; COSMIC: COSV63208190;