1-15112540-G-C

Variant names:

• chr1-15112540-G-C
• rs138289296
• NM_201628.3:c.2162G>C

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_201628.3(KAZN):​c.2162G>C​(p.Arg721Pro) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.000000701 in 1,427,024 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R721Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.0e-7 (0 hom.)
• Consequence: KAZN NM_201628.3 missense, splice_region
• Scores: Splicing: ADA: 0.8492
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.87
• 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]

TMEM51-AS1 (HGNC:26301): (TMEM51 antisense RNA 1)

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.30007017).

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.2162G>C	p.Arg721Pro	missense splice_region	Exon 14 of 15	NP_963922.2	Q674X7-1
	TMEM51-AS1	NR_027136.1		n.6254C>G		non_coding_transcript_exon	Exon 5 of 5

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KAZN	ENST00000376030.7	TSL:5 MANE Select	c.2162G>C	p.Arg721Pro	missense splice_region	Exon 14 of 15	ENSP00000365198.2	Q674X7-1
	TMEM51-AS1	ENST00000404665.4	TSL:1	n.6248C>G		non_coding_transcript_exon	Exon 5 of 5
	KAZN	ENST00000636203.1	TSL:5	c.2426G>C	p.Arg809Pro	missense splice_region	Exon 16 of 17	ENSP00000490958.1	A0A1B0GWK2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 7.01e-7 AC: 1 AN: 1427024 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 706682

African (AFR) AF: 0.00 AC: 0 AN: 32664

American (AMR) AF: 0.00 AC: 0 AN: 41848

Ashkenazi Jewish (ASJ) AF: 0.0000395 AC: 1 AN: 25308

East Asian (EAS) AF: 0.00 AC: 0 AN: 38658

South Asian (SAS) AF: 0.00 AC: 0 AN: 81884

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51898

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5660

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1090318

Other (OTH) AF: 0.00 AC: 0 AN: 58786

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.34
BayesDel_addAF	Benign	-0.062	T
BayesDel_noAF	Benign	-0.33
CADD	Pathogenic	26
DANN	Uncertain	0.99
DEOGEN2	Benign	0.016	T
Eigen	Uncertain	0.45
Eigen_PC	Uncertain	0.47
FATHMM_MKL	Benign	0.74	D
LIST_S2	Benign	0.80	T
M_CAP	Benign	0.016	T
MetaRNN	Benign	0.30	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.9	L
PhyloP100		4.9
PrimateAI	Uncertain	0.50	T
PROVEAN	Benign	-0.53	N
REVEL	Benign	0.16
Sift	Uncertain	0.0030	D
Sift4G	Benign	0.22	T
Polyphen		1.0	D
Vest4		0.59
MutPred		0.36		Loss of MoRF binding (P = 3e-04)
MVP		0.35
MPC		0.49
ClinPred		0.96	D
GERP RS		5.6
Varity_R		0.28
gMVP		0.52
Mutation Taster		=67/33	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.85
dbscSNV1_RF	Benign	0.62
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: rs138289296; hg19: chr1-15439036;