1-145672818-G-C

Position:

• chr1-145672818-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001201325.2(PDZK1):​c.1418C>G​(p.Ser473Cys) variant causes a missense change. The variant allele was found at a frequency of 0.000000685 in 1,459,496 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 28)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: PDZK1 NM_001201325.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.97

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.29116875).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PDZK1	NM_001201325.2	c.1418C>G	p.Ser473Cys	missense_variant	8/9	ENST00000417171.6	NP_001188254.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PDZK1	ENST00000417171.6	c.1418C>G	p.Ser473Cys	missense_variant	8/9	1	NM_001201325.2	ENSP00000394485	P1

Frequencies

GnomAD3 genomes Cov.: 28

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1459496 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 726052

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 28

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 15, 2024

The c.1418C>G (p.S473C) alteration is located in exon 9 (coding exon 7) of the PDZK1 gene. This alteration results from a C to G substitution at nucleotide position 1418, causing the serine (S) at amino acid position 473 to be replaced by a cysteine (C). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_noAF	Pathogenic	0.32
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Benign	0.34	.;T;T
LIST_S2	Benign	0.82	T;T;.
MetaRNN	Benign	0.29	T;T;T
PROVEAN	Benign	-2.1	N;N;N
Sift	Uncertain	0.0060	D;D;D
Sift4G	Benign	0.090	T;D;D
Vest4		0.32
gMVP		0.40

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr1-145762241;