rs9924371

Positions:

• chr16-81220154-A-G

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The ENST00000525539.5(PKD1L2):​c.217T>C​(p.Trp73Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.606 in 1,613,780 control chromosomes in the GnomAD database, including 300,324 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/15 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. W73C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.61 (28360 hom., cov: 32)
  • Exomes 𝑓: 0.61 (271964 hom.)
• Consequence: PKD1L2 ENST00000525539.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.427

Genes affected

PKD1L2 (HGNC:21715): (polycystin 1 like 2 (gene/pseudogene)) This gene encodes a member of the polycystin protein family. This protein may function as a G-protein-coupled component or regulator of cation channel pores. The long isoform of this protein contains 11 transmembrane domains, a latrophilin/CL-1-like GPCR proteolytic site (GPS) domain, and a polycystin-1, lipoxygenase, alpha-toxin (PLAT) domain. Alternative splicing results in multiple transcript variants encoding distinct isoforms. This gene is a polymorphic pseudogene in humans. [provided by RefSeq, May 2022]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=2.1743617E-6).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.631 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PKD1L2	NR_126532.3	n.241T>C		non_coding_transcript_exon_variant	1/43

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PKD1L2	ENST00000525539.5	c.217T>C	p.Trp73Arg	missense_variant	1/43	1		ENSP00000434417

Frequencies

GnomAD3 genomes AF: 0.608 AC: 92260 AN: 151826 Hom.: 28338 Cov.: 32

Gnomad AFR AF: 0.621

Gnomad AMI AF: 0.703

Gnomad AMR AF: 0.569

Gnomad ASJ AF: 0.580

Gnomad EAS AF: 0.404

Gnomad SAS AF: 0.409

Gnomad FIN AF: 0.616

Gnomad MID AF: 0.696

Gnomad NFE AF: 0.636

Gnomad OTH AF: 0.616

GnomAD3 exomes AF: 0.566 AC: 141016 AN: 249318 Hom.: 40979 AF XY: 0.564 AC XY: 76285 AN XY: 135280

Gnomad AFR exome AF: 0.619

Gnomad AMR exome AF: 0.483

Gnomad ASJ exome AF: 0.593

Gnomad EAS exome AF: 0.413

Gnomad SAS exome AF: 0.421

Gnomad FIN exome AF: 0.601

Gnomad NFE exome AF: 0.635

Gnomad OTH exome AF: 0.610

GnomAD4 exome AF: 0.606 AC: 885558 AN: 1461836 Hom.: 271964 Cov.: 63 AF XY: 0.601 AC XY: 436929 AN XY: 727218

Gnomad4 AFR exome AF: 0.619

Gnomad4 AMR exome AF: 0.493

Gnomad4 ASJ exome AF: 0.594

Gnomad4 EAS exome AF: 0.389

Gnomad4 SAS exome AF: 0.421

Gnomad4 FIN exome AF: 0.600

Gnomad4 NFE exome AF: 0.633

Gnomad4 OTH exome AF: 0.598

GnomAD4 genome AF: 0.608 AC: 92329 AN: 151944 Hom.: 28360 Cov.: 32 AF XY: 0.601 AC XY: 44630 AN XY: 74250

Gnomad4 AFR AF: 0.621

Gnomad4 AMR AF: 0.568

Gnomad4 ASJ AF: 0.580

Gnomad4 EAS AF: 0.405

Gnomad4 SAS AF: 0.410

Gnomad4 FIN AF: 0.616

Gnomad4 NFE AF: 0.636

Gnomad4 OTH AF: 0.612

Alfa AF: 0.622 Hom.: 55061

Bravo AF: 0.608

TwinsUK AF: 0.632 AC: 2342

ALSPAC AF: 0.635 AC: 2447

ESP6500AA AF: 0.641 AC: 2615

ESP6500EA AF: 0.632 AC: 5314

ExAC AF: 0.568 AC: 68631

Asia WGS AF: 0.491 AC: 1709 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.65	T
BayesDel_noAF	Benign	-0.56
CADD	Benign	7.1
DANN	Benign	0.20
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.059	N
LIST_S2	Benign	0.032	T
MetaRNN	Benign	0.0000022	T
MetaSVM	Benign	-0.98	T
MutationTaster	Benign	1.0	P
PrimateAI	Benign	0.19	T
PROVEAN	Benign	2.4	N
REVEL	Benign	0.080
Polyphen		0.0	B
Vest4		0.013
MutPred		0.47		Gain of disorder (P = 0.0161);
ClinPred		0.0056	T
GERP RS		-0.11

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

Other links and lift over

dbSNP: rs9924371; hg19: chr16-81253759; COSMIC: COSV61413229;