Genetic Variant PKD2L1:p.Arg681Leu (chr10-100290485-C-A) – ACMG Classification: Benign (-8 pts)

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BA1

The NM_016112.3(PKD2L1):c.2042G>T(p.Arg681Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0605 in 1,612,512 control chromosomes in the GnomAD database, including 3,293 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/23 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 0.069 ( 403 hom., cov: 32)

Exomes 𝑓: 0.060 ( 2890 hom. )

Consequence

PKD2L1
NM_016112.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -1.29

Publications

36 publications found

Variant links:

Genes affected

PKD2L1 (HGNC:9011): (polycystin 2 like 1, transient receptor potential cation channel) This gene encodes a member of the polycystin protein family. The encoded protein contains multiple transmembrane domains, and cytoplasmic N- and C-termini. The protein may be an integral membrane protein involved in cell-cell/matrix interactions. This protein functions as a calcium-regulated nonselective cation channel. Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Dec 2011]

PKD2L1 links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -8 ACMG points.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0967 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PKD2L1	NM_016112.3 link	c.2042G>T	p.Arg681Leu	missense_variant	Exon 13 of 16	ENST00000318222.4	NP_057196.2	Q9P0L9-1
PKD2L1	NM_001253837.2 link	c.1901G>T	p.Arg634Leu	missense_variant	Exon 13 of 16		NP_001240766.1	Q9P0L9Q1L4F0

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
PKD2L1	ENST00000318222.4 link	c.2042G>T	p.Arg681Leu	missense_variant	Exon 13 of 16	1	NM_016112.3	ENSP00000325296.3	Q9P0L9-1
PKD2L1	ENST00000528248.1 link	n.*1782G>T		non_coding_transcript_exon_variant	Exon 13 of 16	1		ENSP00000436514.1	H0YET4
PKD2L1	ENST00000528248.1 link	n.*1782G>T		3_prime_UTR_variant	Exon 13 of 16	1		ENSP00000436514.1	H0YET4
PKD2L1	ENST00000465680.2 link	c.104-2007G>T		intron_variant	Intron 1 of 1	3		ENSP00000434019.1	H0YDN7

Frequencies

GnomAD3 genomes

AF:

0.0690

AC:

10491

AN:

152124

Hom.:

403

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0994

Gnomad AMI

AF:

0.0757

Gnomad AMR

AF:

0.0554

Gnomad ASJ

AF:

0.0662

Gnomad EAS

AF:

0.0560

Gnomad SAS

AF:

0.0710

Gnomad FIN

AF:

0.0615

Gnomad MID

AF:

0.0316

Gnomad NFE

AF:

0.0556

Gnomad OTH

AF:

0.0731

GnomAD2 exomes

AF:

0.0583

AC:

14594

AN:

250460

AF XY:

0.0578

show subpopulations

Gnomad AFR exome

AF:

0.102

Gnomad AMR exome

AF:

0.0512

Gnomad ASJ exome

AF:

0.0653

Gnomad EAS exome

AF:

0.0524

Gnomad FIN exome

AF:

0.0554

Gnomad NFE exome

AF:

0.0522

Gnomad OTH exome

AF:

0.0607

GnomAD4 exome

AF:

0.0597

AC:

87127

AN:

1460270

Hom.:

2890

Cov.:

AF XY:

0.0595

AC XY:

43205

AN XY:

726562

show subpopulations

African (AFR)

AF:

0.102

AC:

3408

AN:

33448

American (AMR)

AF:

0.0521

AC:

2328

AN:

44712

Ashkenazi Jewish (ASJ)

AF:

0.0627

AC:

1637

AN:

26126

East Asian (EAS)

AF:

0.0645

AC:

2560

AN:

39684

South Asian (SAS)

AF:

0.0651

AC:

5618

AN:

86234

European-Finnish (FIN)

AF:

0.0579

AC:

3057

AN:

52788

Middle Eastern (MID)

AF:

0.0507

AC:

292

AN:

5764

European-Non Finnish (NFE)

AF:

0.0577

AC:

64159

AN:

1111160

Other (OTH)

AF:

0.0674

AC:

4068

AN:

60354

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.449

Heterozygous variant carriers

3841

7682

11524

15365

19206

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

2548

5096

7644

10192

12740

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0690

AC:

10498

AN:

152242

Hom.:

403

Cov.:

AF XY:

0.0691

AC XY:

5147

AN XY:

74450

show subpopulations

African (AFR)

AF:

0.0993

AC:

4122

AN:

41524

American (AMR)

AF:

0.0554

AC:

848

AN:

15294

Ashkenazi Jewish (ASJ)

AF:

0.0662

AC:

230

AN:

3472

East Asian (EAS)

AF:

0.0563

AC:

292

AN:

5186

South Asian (SAS)

AF:

0.0708

AC:

342

AN:

4828

European-Finnish (FIN)

AF:

0.0615

AC:

652

AN:

10604

Middle Eastern (MID)

AF:

0.0340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0556

AC:

3780

AN:

68014

Other (OTH)

AF:

0.0724

AC:

153

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

508

1016

1523

2031

2539

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

126

252

378

504

630

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0577

Hom.:

993

Bravo

AF:

0.0701

TwinsUK

AF:

0.0572

AC:

212

ALSPAC

AF:

0.0568

AC:

219

ESP6500AA

AF:

0.0980

AC:

432

ESP6500EA

AF:

0.0549

AC:

472

ExAC

AF:

0.0591

AC:

7173

Asia WGS

AF:

0.0850

AC:

297

AN:

3478

EpiCase

AF:

0.0519

EpiControl

AF:

0.0514

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.090

BayesDel_addAF

Benign

-0.61

BayesDel_noAF

Benign

-0.57

CADD

Benign

0.42

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.35

Eigen

Benign

-1.1

Eigen_PC

Benign

-1.3

FATHMM_MKL

Benign

0.034

LIST_S2

Benign

0.74

MetaRNN

Benign

0.0017

MetaSVM

Benign

-0.90

MutationAssessor

Benign

1.6

PhyloP100

-1.3

PrimateAI

Benign

0.18

PROVEAN

Uncertain

-3.1

REVEL

Benign

0.18

Sift

Uncertain

0.013

Sift4G

Uncertain

0.019

Polyphen

0.046

Vest4

0.056

MPC

0.087

ClinPred

0.045

GERP RS

-6.2

Varity_R

0.11

gMVP

0.15

Mutation Taster

=83/17

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.25

Details are displayed if max score is > 0.2

DS_AL_spliceai

0.25

Position offset: 34

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over