rs6420424

Variant names:

• chr16-81208497-G-A
• rs6420424
• ENST00000525539.5:c.754C>T

Your query was ambiguous. Multiple possible variants found:

• chr16-81208497-G-A
• chr16-81208497-G-C
• chr16-81208497-G-T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The ENST00000525539.5(PKD1L2):​c.754C>T​(p.Arg252Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.498 in 1,551,116 control chromosomes in the GnomAD database, including 200,653 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/18 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 0.49 (19071 hom., cov: 33)
  • Exomes 𝑓: 0.50 (181582 hom.)
• Consequence: PKD1L2 ENST00000525539.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.71
• Publications: 39 publications found

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

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=6.9544905E-7).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.845 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PKD1L2	NR_126532.3	n.778C>T		non_coding_transcript_exon_variant	Exon 4 of 43

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PKD1L2	ENST00000525539.5	c.754C>T	p.Arg252Trp	missense_variant	Exon 4 of 43	1		ENSP00000434417.1

Frequencies

GnomAD3 genomes AF: 0.494 AC: 75011 AN: 151970 Hom.: 19051 Cov.: 33

Gnomad AFR AF: 0.468

Gnomad AMI AF: 0.537

Gnomad AMR AF: 0.486

Gnomad ASJ AF: 0.446

Gnomad EAS AF: 0.865

Gnomad SAS AF: 0.525

Gnomad FIN AF: 0.531

Gnomad MID AF: 0.278

Gnomad NFE AF: 0.479

Gnomad OTH AF: 0.446

GnomAD2 exomes AF: 0.520 AC: 128795 AN: 247542 AF XY: 0.513

Gnomad AFR exome AF: 0.466

Gnomad AMR exome AF: 0.559

Gnomad ASJ exome AF: 0.428

Gnomad EAS exome AF: 0.870

Gnomad FIN exome AF: 0.534

Gnomad NFE exome AF: 0.468

Gnomad OTH exome AF: 0.478

GnomAD4 exome AF: 0.498 AC: 696897 AN: 1399028 Hom.: 181582 Cov.: 31 AF XY: 0.497 AC XY: 347576 AN XY: 698826

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.464 AC: 15246 AN: 32832

American (AMR) AF: 0.549 AC: 24380 AN: 44396

Ashkenazi Jewish (ASJ) AF: 0.423 AC: 10894 AN: 25738

East Asian (EAS) AF: 0.860 AC: 33736 AN: 39240

South Asian (SAS) AF: 0.520 AC: 43964 AN: 84564

European-Finnish (FIN) AF: 0.538 AC: 28581 AN: 53146

Middle Eastern (MID) AF: 0.335 AC: 1897 AN: 5658

European-Non Finnish (NFE) AF: 0.482 AC: 509099 AN: 1055174

Other (OTH) AF: 0.499 AC: 29100 AN: 58280

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.494 AC: 75092 AN: 152088 Hom.: 19071 Cov.: 33 AF XY: 0.497 AC XY: 36911 AN XY: 74340

African (AFR) AF: 0.468 AC: 19415 AN: 41454

American (AMR) AF: 0.486 AC: 7433 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.446 AC: 1549 AN: 3470

East Asian (EAS) AF: 0.866 AC: 4478 AN: 5172

South Asian (SAS) AF: 0.527 AC: 2539 AN: 4818

European-Finnish (FIN) AF: 0.531 AC: 5626 AN: 10586

Middle Eastern (MID) AF: 0.293 AC: 86 AN: 294

European-Non Finnish (NFE) AF: 0.479 AC: 32534 AN: 67984

Other (OTH) AF: 0.447 AC: 942 AN: 2108

Alfa AF: 0.483 Hom.: 86538

Bravo AF: 0.494

TwinsUK AF: 0.496 AC: 1841

ALSPAC AF: 0.484 AC: 1867

ESP6500AA AF: 0.443 AC: 1858

ESP6500EA AF: 0.469 AC: 3958

ExAC AF: 0.517 AC: 62512

Asia WGS AF: 0.682 AC: 2370 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.074
BayesDel_addAF	Benign	-0.62	T
BayesDel_noAF	Benign	-0.53
CADD	Benign	20
DANN	Benign	0.86
Eigen	Benign	-0.93
Eigen_PC	Benign	-0.88
FATHMM_MKL	Benign	0.42	N
LIST_S2	Benign	0.56	T
MetaRNN	Benign	7.0e-7	T
MetaSVM	Benign	-1.0	T
PhyloP100		1.7
PrimateAI	Benign	0.18	T
PROVEAN	Benign	-1.4	N
REVEL	Benign	0.14
Polyphen		0.015	B
Vest4		0.19
ClinPred		0.0047	T
GERP RS		2.0
Mutation Taster		=97/3	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs6420424; hg19: chr16-81242102; COSMIC: COSV61415384;