2-178451764-C-G

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_001042702.5(PJVK):c.-28C>G variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00745 in 985,344 control chromosomes in the GnomAD database, including 304 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.030 (209 hom., cov: 32)
  • Exomes 𝑓: 0.0033 (95 hom.)
• Consequence: PJVK NM_001042702.5 5_prime_UTR
• Clinical Significance: Likely benign criteria provided, single submitter B:2
• Conservation: PhyloP100: -1.19

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]

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BP6: Variant 2-178451764-C-G is Benign according to our data. Variant chr2-178451764-C-G is described in ClinVar as [Likely_benign]. Clinvar id is 369319.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0947 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PJVK	NM_001042702.5	c.-28C>G		5_prime_UTR_variant	1/7	ENST00000644580.2
PJVK	NM_001353775.2	c.-77C>G		5_prime_UTR_variant	1/7
PJVK	NM_001353777.1	c.-340C>G		5_prime_UTR_variant	1/7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PJVK	ENST00000644580.2	c.-28C>G		5_prime_UTR_variant	1/7		NM_001042702.5	P1

Frequencies

GnomAD3 genomes AF: 0.0299 AC: 4555 AN: 152160 Hom.: 208 Cov.: 32

Gnomad AFR AF: 0.0972

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0150

Gnomad ASJ AF: 0.0369

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000828

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0190

Gnomad NFE AF: 0.00148

Gnomad OTH AF: 0.0278

GnomAD4 exome AF: 0.00333 AC: 2776 AN: 833066 Hom.: 95 Cov.: 29 AF XY: 0.00323 AC XY: 1241 AN XY: 384710

Gnomad4 AFR exome AF: 0.108

Gnomad4 AMR exome AF: 0.00815

Gnomad4 ASJ exome AF: 0.0344

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000304

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000786

Gnomad4 OTH exome AF: 0.00905

GnomAD4 genome AF: 0.0300 AC: 4563 AN: 152278 Hom.: 209 Cov.: 32 AF XY: 0.0291 AC XY: 2167 AN XY: 74468

Gnomad4 AFR AF: 0.0972

Gnomad4 AMR AF: 0.0150

Gnomad4 ASJ AF: 0.0369

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000621

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00149

Gnomad4 OTH AF: 0.0275

Alfa AF: 0.0245 Hom.: 19

Bravo AF: 0.0352

Asia WGS AF: 0.00549 AC: 19 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, single submitter

Submissions by phenotype

Dystonic disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Autosomal recessive nonsyndromic hearing loss 59 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
Cadd	Benign	0.90
Dann	Benign	0.47

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.090		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs74808009; hg19: chr2-179316491;