ENST00000525539.5:c.59T>C

Variant names:

• chr16-81220312-A-G
• rs9924530
• ENST00000525539.5:c.59T>C
• PKD1L2 p.Val20Ala

Variant summary

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

The ENST00000525539.5(PKD1L2):​c.59T>C​(p.Val20Ala) 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 1,613,564 control chromosomes in the GnomAD database, including 300,370 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. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V20G) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.61 (28377 hom., cov: 32)
  • Exomes 𝑓: 0.61 (271993 hom.)
• Consequence: PKD1L2 ENST00000525539.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.18
• Publications: 24 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=1.08696E-5).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.631 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000525539.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PKD1L2	NR_126532.3		n.83T>C		non_coding_transcript_exon	Exon 1 of 43

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PKD1L2	ENST00000525539.5	TSL:1	c.59T>C	p.Val20Ala	missense	Exon 1 of 43	ENSP00000434417.1

Frequencies

GnomAD3 genomes AF: 0.608 AC: 92309 AN: 151758 Hom.: 28355 Cov.: 32

Gnomad AFR AF: 0.623

Gnomad AMI AF: 0.705

Gnomad AMR AF: 0.569

Gnomad ASJ AF: 0.579

Gnomad EAS AF: 0.404

Gnomad SAS AF: 0.408

Gnomad FIN AF: 0.615

Gnomad MID AF: 0.696

Gnomad NFE AF: 0.636

Gnomad OTH AF: 0.617

GnomAD2 exomes AF: 0.565 AC: 140406 AN: 248354 AF XY: 0.564

Gnomad AFR exome AF: 0.619

Gnomad AMR exome AF: 0.483

Gnomad ASJ exome AF: 0.593

Gnomad EAS exome AF: 0.412

Gnomad FIN exome AF: 0.601

Gnomad NFE exome AF: 0.635

Gnomad OTH exome AF: 0.610

GnomAD4 exome AF: 0.606 AC: 885591 AN: 1461690 Hom.: 271993 Cov.: 67 AF XY: 0.601 AC XY: 436951 AN XY: 727152

African (AFR) AF: 0.620 AC: 20722 AN: 33396

American (AMR) AF: 0.493 AC: 22053 AN: 44702

Ashkenazi Jewish (ASJ) AF: 0.593 AC: 15508 AN: 26136

East Asian (EAS) AF: 0.388 AC: 15421 AN: 39696

South Asian (SAS) AF: 0.421 AC: 36344 AN: 86258

European-Finnish (FIN) AF: 0.600 AC: 32065 AN: 53418

Middle Eastern (MID) AF: 0.665 AC: 3829 AN: 5756

European-Non Finnish (NFE) AF: 0.633 AC: 703547 AN: 1111956

Other (OTH) AF: 0.598 AC: 36102 AN: 60372

GnomAD4 genome AF: 0.608 AC: 92378 AN: 151874 Hom.: 28377 Cov.: 32 AF XY: 0.602 AC XY: 44659 AN XY: 74228

African (AFR) AF: 0.623 AC: 25721 AN: 41264

American (AMR) AF: 0.569 AC: 8680 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.579 AC: 2008 AN: 3466

East Asian (EAS) AF: 0.405 AC: 2094 AN: 5174

South Asian (SAS) AF: 0.410 AC: 1978 AN: 4828

European-Finnish (FIN) AF: 0.615 AC: 6513 AN: 10588

Middle Eastern (MID) AF: 0.684 AC: 201 AN: 294

European-Non Finnish (NFE) AF: 0.636 AC: 43253 AN: 67980

Other (OTH) AF: 0.613 AC: 1288 AN: 2102

Alfa AF: 0.621 Hom.: 28713

Bravo AF: 0.608

Asia WGS AF: 0.491 AC: 1708 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.056
BayesDel_addAF	Benign	-0.72	T
BayesDel_noAF	Benign	-0.67
CADD	Benign	7.0
DANN	Benign	0.12
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.0014	N
LIST_S2	Benign	0.13	T
MetaRNN	Benign	0.000011	T
MetaSVM	Benign	-0.94	T
PhyloP100		1.2
PrimateAI	Benign	0.41	T
PROVEAN	Benign	1.5	N
REVEL	Benign	0.020
PromoterAI		0.00080	Neutral
Mutation Taster		=100/0	polymorphism (auto)

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs9924530;

hg19: chr16-81253917;

COSMIC: COSV61413270;