Genetic Variant KAZN:p.Arg721Arg (chr1-15112541-G-A) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_201628.3(KAZN):c.2163G>A(p.Arg721Arg) variant causes a splice region, synonymous change. The variant allele was found at a frequency of 0.000000693 in 1,443,530 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

KAZN
NM_201628.3 splice_region, synonymous

Scores

Splicing: ADA: 0.4350

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 4.87

Publications

0 publications found

Variant links:

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]

KAZN links:

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

TMEM51-AS1 links:

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ACMG classification

Classification was made for transcript

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 (BayesDel_noAF=-0.41).

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.2163G>A	p.Arg721Arg	splice_region synonymous	Exon 14 of 15	NP_963922.2	Q674X7-1
	TMEM51-AS1	NR_027136.1		n.6253C>T		non_coding_transcript_exon	Exon 5 of 5

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
KAZN	ENST00000376030.7	TSL:5 MANE Select	c.2163G>A	p.Arg721Arg	splice_region synonymous	Exon 14 of 15	ENSP00000365198.2	Q674X7-1
TMEM51-AS1	ENST00000404665.4	TSL:1	n.6247C>T		non_coding_transcript_exon	Exon 5 of 5
KAZN	ENST00000636203.1	TSL:5	c.2427G>A	p.Arg809Arg	splice_region synonymous	Exon 16 of 17	ENSP00000490958.1	A0A1B0GWK2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.93e-7

AC:

AN:

1443530

Hom.:

Cov.:

AF XY:

0.00000140

AC XY:

AN XY:

716460

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

33192

American (AMR)

AF:

0.00

AC:

AN:

42208

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25734

East Asian (EAS)

AF:

0.00

AC:

AN:

38968

South Asian (SAS)

AF:

0.00

AC:

AN:

82978

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52490

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5742

European-Non Finnish (NFE)

AF:

9.07e-7

AC:

AN:

1102468

Other (OTH)

AF:

0.00

AC:

AN:

59750

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.375

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.41

CADD

Benign

(source)

DANN

Benign

0.91

PhyloP100

4.9

Mutation Taster

=48/52

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.44

dbscSNV1_RF

Benign

0.47

SpliceAI score (max)

0.23

Details are displayed if max score is > 0.2

DS_DG_spliceai

0.23

Position offset: 24

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over