chr2-178454525-A-C

Variant names:

• chr2-178454525-A-C
• rs373800401
• NM_001042702.5:c.405A>C

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Moderate BP6 BP7

The NM_001353775.2(PJVK):​c.414A>C​(p.Thr138Thr) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000121 in 1,612,778 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. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.000085 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00012 (0 hom.)
• Consequence: PJVK NM_001353775.2 splice_region, synonymous
• Scores: Splicing: ADA: 0.0004640
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:3
• Conservation: PhyloP100: 0.914
• 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]

NUDCP2 (HGNC:8047): (nuclear distribution C pseudogene 2)

ACMG classification

Our verdict: Likely_benign. The variant received -4 ACMG points.

• BP4: Computational evidence support a benign effect (REVEL=0.057).
• BP6: Variant 2-178454525-A-C is Benign according to our data. Variant chr2-178454525-A-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 163062.
• BP7: Synonymous conserved (PhyloP=0.914 with no splicing effect.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001353775.2. 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.405A>C	p.Thr135Thr	splice_region synonymous	Exon 3 of 7	NP_001036167.1
	PJVK	NM_001353777.1		c.-73A>C		splice_region	Exon 3 of 7	NP_001340706.1
	PJVK	NM_001353778.2		c.-73A>C		splice_region	Exon 3 of 7	NP_001340707.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PJVK	ENST00000644580.2	MANE Select	c.405A>C	p.Thr135Thr	splice_region synonymous	Exon 3 of 7	ENSP00000495855.2
	PJVK	ENST00000375129.8	TSL:1	c.405A>C	p.Thr135Thr	splice_region synonymous	Exon 2 of 6	ENSP00000364271.4
	PJVK	ENST00000437056.5	TSL:1	n.1275A>C		splice_region non_coding_transcript_exon	Exon 1 of 5

Frequencies

GnomAD3 genomes AF: 0.0000854 AC: 13 AN: 152182 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000176

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000604 AC: 15 AN: 248180 AF XY: 0.0000520

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000467

Gnomad NFE exome AF: 0.000125

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000125 AC: 182 AN: 1460596 Hom.: 0 Cov.: 30 AF XY: 0.000111 AC XY: 81 AN XY: 726632

African (AFR) AF: 0.00 AC: 0 AN: 33456

American (AMR) AF: 0.0000224 AC: 1 AN: 44678

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26080

East Asian (EAS) AF: 0.00 AC: 0 AN: 39628

South Asian (SAS) AF: 0.00 AC: 0 AN: 86102

European-Finnish (FIN) AF: 0.0000188 AC: 1 AN: 53194

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5714

European-Non Finnish (NFE) AF: 0.000155 AC: 172 AN: 1111390

Other (OTH) AF: 0.000133 AC: 8 AN: 60354

GnomAD4 genome AF: 0.0000854 AC: 13 AN: 152182 Hom.: 0 Cov.: 33 AF XY: 0.000108 AC XY: 8 AN XY: 74354

African (AFR) AF: 0.0000241 AC: 1 AN: 41442

American (AMR) AF: 0.00 AC: 0 AN: 15274

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5200

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10608

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.000176 AC: 12 AN: 68032

Other (OTH) AF: 0.00 AC: 0 AN: 2094

Alfa AF: 0.000143 Hom.: 0

Bravo AF: 0.000110

EpiCase AF: 0.000109

EpiControl AF: 0.0000594

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	-	Autosomal recessive nonsyndromic hearing loss 59 (1)
-	-	1	not provided (1)
-	-	1	not specified (1)
-	-	1	PJVK-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.42
CADD	Benign	6.6
DANN	Benign	0.75
PhyloP100		0.91
Mutation Taster		=88/12	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00046
dbscSNV1_RF	Benign	0.036
SpliceAI score (max)		0.020		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: rs373800401; hg19: chr2-179319252;