2-178453333-C-T

Variant names:

• chr2-178453333-C-T
• rs77758075
• ENST00000375129.8:c.-77C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001369912.1(PJVK):​c.-77C>T variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00108 in 1,438,228 control chromosomes in the GnomAD database, including 17 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0055 (10 hom., cov: 33)
  • Exomes 𝑓: 0.00056 (7 hom.)
• Consequence: PJVK NM_001369912.1 5_prime_UTR
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.365
• Publications: 0 publications found

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

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.56).
• BP6: Variant 2-178453333-C-T is Benign according to our data. Variant chr2-178453333-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 1214892.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00546 (831/152272) while in subpopulation AFR AF = 0.0192 (798/41546). AF 95% confidence interval is 0.0181. There are 10 homozygotes in GnomAd4. There are 399 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 10 AR gene

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

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

Ensembl Transcripts

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

Frequencies

GnomAD3 genomes AF: 0.00544 AC: 827 AN: 152154 Hom.: 10 Cov.: 33

Gnomad AFR AF: 0.0192

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00111

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000118

Gnomad OTH AF: 0.00287

GnomAD4 exome AF: 0.000559 AC: 719 AN: 1285956 Hom.: 7 Cov.: 18 AF XY: 0.000467 AC XY: 303 AN XY: 648238

African (AFR) AF: 0.0202 AC: 597 AN: 29590

American (AMR) AF: 0.000950 AC: 41 AN: 43138

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24840

East Asian (EAS) AF: 0.00 AC: 0 AN: 38196

South Asian (SAS) AF: 0.0000621 AC: 5 AN: 80542

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52346

Middle Eastern (MID) AF: 0.000554 AC: 3 AN: 5412

European-Non Finnish (NFE) AF: 0.0000146 AC: 14 AN: 957682

Other (OTH) AF: 0.00109 AC: 59 AN: 54210

GnomAD4 genome AF: 0.00546 AC: 831 AN: 152272 Hom.: 10 Cov.: 33 AF XY: 0.00536 AC XY: 399 AN XY: 74460

African (AFR) AF: 0.0192 AC: 798 AN: 41546

American (AMR) AF: 0.00111 AC: 17 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

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

South Asian (SAS) AF: 0.000414 AC: 2 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10604

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

European-Non Finnish (NFE) AF: 0.000118 AC: 8 AN: 68002

Other (OTH) AF: 0.00284 AC: 6 AN: 2116

Alfa AF: 0.00354 Hom.: 1

Bravo AF: 0.00662

Asia WGS AF: 0.000866 AC: 3 AN: 3478

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.56
CADD	Benign	9.3
DANN	Benign	0.78
PhyloP100		-0.36
PromoterAI		0.00050	Neutral
Mutation Taster		=299/1	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: rs77758075; hg19: chr2-179318060;