Variant chr1-145686641-C-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_001201325.2(PDZK1):c.296G>A(p.Arg99Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000332 in 1,595,262 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 8/12 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.000033 ( 0 hom., cov: 29)

Exomes 𝑓: 0.000033 ( 0 hom. )

Consequence

PDZK1
NM_001201325.2 missense

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: 0.0320

Variant links:

Genes affected

PDZK1 (HGNC:8821): (PDZ domain containing 1) This gene encodes a PDZ domain-containing scaffolding protein. PDZ domain-containing molecules bind to and mediate the subcellular localization of target proteins. The encoded protein mediates the localization of cell surface proteins and plays a critical role in cholesterol metabolism by regulating the HDL receptor, scavenger receptor class B type 1. Single nucleotide polymorphisms in this gene may be associated with metabolic syndrome, and overexpression of this gene may play a role in drug resistance of multiple myeloma. Pseudogenes of this gene are located on the long arm of chromosome 1. Alternatively spliced transcript variants encoding multiple isoforms have been observed for this gene. [provided by RefSeq, Jan 2011]

PDZK1 links:

PDZK1 (HGNC:):

PDZK1 links:

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.047849506).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PDZK1	NM_001201325.2 linkuse as main transcript	c.296G>A	p.Arg99Gln	missense_variant	3/9	ENST00000417171.6	NP_001188254.1	Q5T2W1-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
PDZK1	ENST00000417171.6 linkuse as main transcript	c.296G>A	p.Arg99Gln	missense_variant	3/9	1	NM_001201325.2	ENSP00000394485.1	Q5T2W1-1
PDZK1	ENST00000344770.6 linkuse as main transcript	c.296G>A	p.Arg99Gln	missense_variant	3/9	5		ENSP00000342143.2	Q5T2W1-1
PDZK1	ENST00000451928.6 linkuse as main transcript	c.296G>A	p.Arg99Gln	missense_variant	3/7	2		ENSP00000403422.2	Q5T2W1-2
PDZK1	ENST00000443667.1 linkuse as main transcript	c.296G>A	p.Arg99Gln	missense_variant	4/6	5		ENSP00000409291.1	A0A0C4DG67

Frequencies

GnomAD3 genomes

AF:

0.0000330

AC:

AN:

151664

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

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:

0.0000736

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000496

AC:

AN:

221776

Hom.:

AF XY:

0.0000665

AC XY:

AN XY:

120220

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000647

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000351

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000716

Gnomad OTH exome

AF:

0.000181

GnomAD4 exome

AF:

0.0000333

AC:

AN:

1443480

Hom.:

Cov.:

AF XY:

0.0000488

AC XY:

AN XY:

717642

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000463

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000254

Gnomad4 SAS exome

AF:

0.0000470

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000327

Gnomad4 OTH exome

AF:

0.0000670

GnomAD4 genome

AF:

0.0000329

AC:

AN:

151782

Hom.:

Cov.:

AF XY:

0.0000270

AC XY:

AN XY:

74150

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000736

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000130

Hom.:

Bravo

AF:

0.0000340

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 25, 2024

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.060

BayesDel_noAF

Benign

-0.83

CADD

Benign

1.3

DANN

Benign

0.32

DEOGEN2

Benign

0.094

.;T;T;.

LIST_S2

Benign

0.66

T;T;.;T

MetaRNN

Benign

0.048

T;T;T;T

PROVEAN

Benign

-0.040

N;N;N;N

Sift

Benign

0.28

T;T;T;T

Sift4G

Benign

0.46

T;T;T;.

Vest4

0.095

gMVP

0.64

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over