Genetic Variant PJVK:c.-77C>A (chr2-178453333-C-A) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_001369912.1(PJVK):c.-77C>A variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000156 in 1,285,958 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000016 ( 0 hom. )

Consequence

PJVK
NM_001369912.1 5_prime_UTR

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.365

Publications

0 publications found

Variant links:

Genes affected

PJVK (HGNC:29502): (pejvakin) The protein encoded by this gene is a member of the gasdermin family, a family which is found only in vertebrates. The encoded protein is required for the proper function of auditory pathway neurons. Defects in this gene are a cause of non-syndromic sensorineural deafness autosomal recessive type 59 (DFNB59). [provided by RefSeq, Dec 2008]

PJVK Gene-Disease associations (from GenCC):

autosomal recessive nonsyndromic hearing loss 59
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae)
nonsyndromic genetic hearing loss
Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
hearing loss, autosomal recessive
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

PJVK links:

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ACMG classification

Classification was made for transcript

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 (BayesDel_noAF=-0.54).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001369912.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
PJVK	NM_001042702.5	MANE Select	c.-22-55C>A	intron	N/A	NP_001036167.1	Q0ZLH3
PJVK	NM_001369912.1		c.-77C>A	5_prime_UTR	Exon 1 of 6	NP_001356841.1	Q0ZLH3
PJVK	NM_001353775.2		c.31-98C>A	intron	N/A	NP_001340704.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
PJVK	ENST00000375129.8	TSL:1	c.-77C>A	5_prime_UTR	Exon 1 of 6	ENSP00000364271.4	Q0ZLH3
PJVK	ENST00000644580.2	MANE Select	c.-22-55C>A	intron	N/A	ENSP00000495855.2	Q0ZLH3
PJVK	ENST00000437056.5	TSL:1	n.83C>A	non_coding_transcript_exon	Exon 1 of 5

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000156

AC:

AN:

1285958

Hom.:

Cov.:

AF XY:

0.00000154

AC XY:

AN XY:

648240

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:

29592

American (AMR)

AF:

0.00

AC:

AN:

43138

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24840

East Asian (EAS)

AF:

0.00

AC:

AN:

38196

South Asian (SAS)

AF:

0.00

AC:

AN:

80542

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52346

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5412

European-Non Finnish (NFE)

AF:

0.00000209

AC:

AN:

957682

Other (OTH)

AF:

0.00

AC:

AN:

54210

⚠️ 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: 0.225

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

-0.54

CADD

Benign

8.1

(source)

DANN

Benign

0.75

PhyloP100

-0.36

PromoterAI

-0.011

Neutral

(source)

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

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