dbSNP rs185220846: PJVK:c.766+8T>C (chr2-178460454-T-C) – ACMG Classification: Benign (-13 pts)

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_001042702.5(PJVK):c.766+8T>C variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00162 in 1,608,602 control chromosomes in the GnomAD database, including 51 homozygotes. 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 0.0015 ( 5 hom., cov: 32)

Exomes 𝑓: 0.0016 ( 46 hom. )

Consequence

PJVK
NM_001042702.5 splice_region, intron

Scores

Splicing: ADA: 0.0001418

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:4

Conservation

PhyloP100: -0.603

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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -13 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.87).

BP6

Variant 2-178460454-T-C is Benign according to our data. Variant chr2-178460454-T-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 178339.

BS1

Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.00146 (222/152318) while in subpopulation SAS AF = 0.0224 (108/4822). AF 95% confidence interval is 0.019. There are 5 homozygotes in GnomAd4. There are 122 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 5 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001042702.5. 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.766+8T>C	splice_region intron	N/A	NP_001036167.1	Q0ZLH3
PJVK	NM_001353775.2		c.775+8T>C	splice_region intron	N/A	NP_001340704.1
PJVK	NM_001353776.2		c.773-528T>C	intron	N/A	NP_001340705.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
PJVK	ENST00000644580.2	MANE Select	c.766+8T>C	splice_region intron	N/A	ENSP00000495855.2	Q0ZLH3
PJVK	ENST00000375129.8	TSL:1	c.766+8T>C	splice_region intron	N/A	ENSP00000364271.4	Q0ZLH3
PJVK	ENST00000437056.5	TSL:1	n.1636+8T>C	splice_region intron	N/A

Frequencies

GnomAD3 genomes

AF:

0.00144

AC:

219

AN:

152200

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000169

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00157

Gnomad ASJ

AF:

0.00115

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.0218

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00112

Gnomad OTH

AF:

0.00143

GnomAD2 exomes

AF:

0.00285

AC:

711

AN:

249194

AF XY:

0.00374

show subpopulations

Gnomad AFR exome

AF:

0.000129

Gnomad AMR exome

AF:

0.000551

Gnomad ASJ exome

AF:

0.00129

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00102

Gnomad OTH exome

AF:

0.00231

GnomAD4 exome

AF:

0.00164

AC:

2384

AN:

1456284

Hom.:

Cov.:

AF XY:

0.00221

AC XY:

1599

AN XY:

724884

show subpopulations

African (AFR)

AF:

0.000239

AC:

AN:

33406

American (AMR)

AF:

0.000559

AC:

AN:

44712

Ashkenazi Jewish (ASJ)

AF:

0.00153

AC:

AN:

26096

East Asian (EAS)

AF:

0.000101

AC:

AN:

39638

South Asian (SAS)

AF:

0.0182

AC:

1567

AN:

86122

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53378

Middle Eastern (MID)

AF:

0.00330

AC:

AN:

5758

European-Non Finnish (NFE)

AF:

0.000519

AC:

575

AN:

1106982

Other (OTH)

AF:

0.00243

AC:

146

AN:

60192

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.472

Heterozygous variant carriers

103

206

308

411

514

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

120

150

<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

AF:

0.00146

AC:

222

AN:

152318

Hom.:

Cov.:

AF XY:

0.00164

AC XY:

122

AN XY:

74488

show subpopulations

African (AFR)

AF:

0.000168

AC:

AN:

41574

American (AMR)

AF:

0.00157

AC:

AN:

15300

Ashkenazi Jewish (ASJ)

AF:

0.00115

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5188

South Asian (SAS)

AF:

0.0224

AC:

108

AN:

4822

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10610

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00112

AC:

AN:

68032

Other (OTH)

AF:

0.00142

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.511

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

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

Alfa

AF:

0.000741

Hom.:

Bravo

AF:

0.000714

Asia WGS

AF:

0.0110

AC:

AN:

3478

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

not specified (2)

Autosomal recessive nonsyndromic hearing loss 59 (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.87

CADD

Benign

1.6

(source)

DANN

Benign

0.71

PhyloP100

-0.60

Mutation Taster

=100/0

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.00014

dbscSNV1_RF

Benign

0.0020

SpliceAI score (max)

0.010

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

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over