Genetic Variant PRKCSH:c.-130C>T (chr19-11435654-C-T) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_001289104.2(PRKCSH):c.-130C>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 0.00936 in 1,286,194 control chromosomes in the GnomAD database, including 76 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.0074 ( 11 hom., cov: 33)

Exomes 𝑓: 0.0096 ( 65 hom. )

Consequence

PRKCSH
NM_001289104.2 5_prime_UTR

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: -0.145

Publications

2 publications found

Variant links:

Genes affected

PRKCSH (HGNC:9411): (PRKCSH beta subunit of glucosidase II) This gene encodes the beta-subunit of glucosidase II, an N-linked glycan-processing enzyme in the endoplasmic reticulum. The encoded protein is an acidic phosphoprotein known to be a substrate for protein kinase C. Mutations in this gene have been associated with the autosomal dominant polycystic liver disease. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jan 2014]

PRKCSH links:

ODAD3 (HGNC:28303): (outer dynein arm docking complex subunit 3) This gene encodes a protein containing coiled-coil domains. The encoded protein functions in outer dynein arm assembly and is required for motile cilia function. Mutations in this gene result in primary ciliary dyskinesia. Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Oct 2014]

ODAD3 Gene-Disease associations (from GenCC):

primary ciliary dyskinesia 30
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: ClinGen, Labcorp Genetics (formerly Invitae), G2P
primary ciliary dyskinesia
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ODAD3 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.61).

BP6

Variant 19-11435654-C-T is Benign according to our data. Variant chr19-11435654-C-T is described in ClinVar as Benign. ClinVar VariationId is 328166.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00736 (1121/152296) while in subpopulation NFE AF = 0.0107 (729/68026). AF 95% confidence interval is 0.0101. There are 11 homozygotes in GnomAd4. There are 537 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High AC in GnomAd4 at 1121 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001289104.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
PRKCSH	NM_001289104.2	MANE Select	c.-130C>T	5_prime_UTR	Exon 1 of 18	NP_001276033.1	K7ELL7
PRKCSH	NM_001289103.2		c.-134C>T	5_prime_UTR	Exon 1 of 18	NP_001276032.1	K7ELL7
PRKCSH	NM_001379608.1		c.-134C>T	5_prime_UTR	Exon 1 of 18	NP_001366537.1	P14314-1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
PRKCSH	ENST00000677123.1	MANE Select	c.-130C>T	5_prime_UTR	Exon 1 of 18	ENSP00000503163.1	K7ELL7
PRKCSH	ENST00000592741.5	TSL:1	c.-134C>T	5_prime_UTR	Exon 1 of 18	ENSP00000466134.1	K7ELL7
PRKCSH	ENST00000951516.1		c.-134C>T	5_prime_UTR	Exon 1 of 18	ENSP00000621575.1

Frequencies

GnomAD3 genomes

AF:

0.00736

AC:

1120

AN:

152176

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00181

Gnomad AMI

AF:

0.0582

Gnomad AMR

AF:

0.00786

Gnomad ASJ

AF:

0.00663

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00166

Gnomad FIN

AF:

0.00792

Gnomad MID

AF:

0.0127

Gnomad NFE

AF:

0.0107

Gnomad OTH

AF:

0.0120

GnomAD2 exomes

AF:

0.00643

AC:

838

AN:

130294

AF XY:

0.00608

show subpopulations

Gnomad AFR exome

AF:

0.00230

Gnomad AMR exome

AF:

0.00505

Gnomad ASJ exome

AF:

0.00593

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00762

Gnomad NFE exome

AF:

0.0106

Gnomad OTH exome

AF:

0.0135

GnomAD4 exome

AF:

0.00963

AC:

10922

AN:

1133898

Hom.:

Cov.:

AF XY:

0.00933

AC XY:

5196

AN XY:

557024

show subpopulations

African (AFR)

AF:

0.00163

AC:

AN:

24530

American (AMR)

AF:

0.00531

AC:

151

AN:

28460

Ashkenazi Jewish (ASJ)

AF:

0.00565

AC:

AN:

16288

East Asian (EAS)

AF:

0.00

AC:

AN:

13124

South Asian (SAS)

AF:

0.00183

AC:

139

AN:

76020

European-Finnish (FIN)

AF:

0.0103

AC:

134

AN:

12976

Middle Eastern (MID)

AF:

0.0119

AC:

AN:

4354

European-Non Finnish (NFE)

AF:

0.0109

AC:

9976

AN:

916412

Other (OTH)

AF:

0.00810

AC:

338

AN:

41734

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.494

Heterozygous variant carriers

498

996

1494

1992

2490

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

434

868

1302

1736

2170

<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:

0.00736

AC:

1121

AN:

152296

Hom.:

Cov.:

AF XY:

0.00721

AC XY:

537

AN XY:

74470

show subpopulations

African (AFR)

AF:

0.00180

AC:

AN:

41578

American (AMR)

AF:

0.00785

AC:

120

AN:

15280

Ashkenazi Jewish (ASJ)

AF:

0.00663

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5190

South Asian (SAS)

AF:

0.00166

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.00792

AC:

AN:

10612

Middle Eastern (MID)

AF:

0.0136

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0107

AC:

729

AN:

68026

Other (OTH)

AF:

0.0118

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

103

154

206

257

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<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:

0.00589

Hom.:

Bravo

AF:

0.00774

Asia WGS

AF:

0.00260

AC:

AN:

3478

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (1)

Polycystic liver disease 1 (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.61

CADD

Benign

7.5

(source)

DANN

Benign

0.92

PhyloP100

-0.14

PromoterAI

-0.12

Neutral

(source)

Mutation Taster

=300/0

polymorphism

(source)

Splicing

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