Genetic Variant PKD1L2:p.Arg849His (chr16-81175642-C-T) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The ENST00000525539.5(PKD1L2):c.2546G>A(p.Arg849His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0324 in 1,613,926 control chromosomes in the GnomAD database, including 1,003 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. R849C) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.026 ( 75 hom., cov: 32)

Exomes 𝑓: 0.033 ( 928 hom. )

Consequence

PKD1L2
ENST00000525539.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -2.47

Publications

14 publications found

Variant links:

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]

PKD1L2 links:

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ACMG classification

Classification was made for transcript

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

BP4

Computational evidence support a benign effect (MetaRNN=0.00234133).

BA1

GnomAdExome4 highest subpopulation (MID) allele frequency at 95% confidence interval = 0.0583 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PKD1L2	NR_126532.3 link	n.2561G>A		non_coding_transcript_exon_variant	Exon 15 of 43

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PKD1L2	ENST00000525539.5 link	c.2546G>A	p.Arg849His	missense_variant	Exon 15 of 43	1		ENSP00000434417.1

Frequencies

GnomAD3 genomes

AF:

0.0255

AC:

3884

AN:

152164

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00623

Gnomad AMI

AF:

0.0735

Gnomad AMR

AF:

0.0252

Gnomad ASJ

AF:

0.0392

Gnomad EAS

AF:

0.000385

Gnomad SAS

AF:

0.0300

Gnomad FIN

AF:

0.0273

Gnomad MID

AF:

0.0443

Gnomad NFE

AF:

0.0370

Gnomad OTH

AF:

0.0320

GnomAD2 exomes

AF:

0.0273

AC:

6806

AN:

249574

AF XY:

0.0291

show subpopulations

Gnomad AFR exome

AF:

0.00530

Gnomad AMR exome

AF:

0.0149

Gnomad ASJ exome

AF:

0.0424

Gnomad EAS exome

AF:

0.000167

Gnomad FIN exome

AF:

0.0281

Gnomad NFE exome

AF:

0.0367

Gnomad OTH exome

AF:

0.0346

GnomAD4 exome

AF:

0.0331

AC:

48386

AN:

1461644

Hom.:

928

Cov.:

AF XY:

0.0337

AC XY:

24469

AN XY:

727100

show subpopulations

African (AFR)

AF:

0.00606

AC:

203

AN:

33478

American (AMR)

AF:

0.0160

AC:

714

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.0400

AC:

1046

AN:

26132

East Asian (EAS)

AF:

0.000151

AC:

AN:

39700

South Asian (SAS)

AF:

0.0276

AC:

2379

AN:

86248

European-Finnish (FIN)

AF:

0.0283

AC:

1514

AN:

53420

Middle Eastern (MID)

AF:

0.0637

AC:

366

AN:

5746

European-Non Finnish (NFE)

AF:

0.0363

AC:

40325

AN:

1111812

Other (OTH)

AF:

0.0304

AC:

1833

AN:

60384

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.450

Heterozygous variant carriers

2432

4864

7295

9727

12159

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1456

2912

4368

5824

7280

<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:

0.0255

AC:

3884

AN:

152282

Hom.:

Cov.:

AF XY:

0.0251

AC XY:

1872

AN XY:

74464

show subpopulations

African (AFR)

AF:

0.00623

AC:

259

AN:

41550

American (AMR)

AF:

0.0252

AC:

385

AN:

15282

Ashkenazi Jewish (ASJ)

AF:

0.0392

AC:

136

AN:

3470

East Asian (EAS)

AF:

0.000386

AC:

AN:

5184

South Asian (SAS)

AF:

0.0303

AC:

146

AN:

4826

European-Finnish (FIN)

AF:

0.0273

AC:

290

AN:

10620

Middle Eastern (MID)

AF:

0.0408

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0370

AC:

2520

AN:

68030

Other (OTH)

AF:

0.0317

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

202

404

605

807

1009

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

144

192

240

<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:

0.0328

Hom.:

302

Bravo

AF:

0.0247

TwinsUK

AF:

0.0386

AC:

143

ESP6500AA

AF:

0.00758

AC:

ESP6500EA

AF:

0.0361

AC:

304

ExAC

AF:

0.0276

AC:

3341

Asia WGS

AF:

0.0120

AC:

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.076

BayesDel_addAF

Benign

-0.45

BayesDel_noAF

Benign

-0.39

CADD

Benign

0.11

(source)

DANN

Benign

0.85

DEOGEN2

Benign

0.0

.;.;.

Eigen

Benign

-1.7

Eigen_PC

Benign

-1.8

LIST_S2

Benign

0.59

T;T;T

MetaRNN

Benign

0.0023

T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.0

.;.;.

PhyloP100

-2.5

PrimateAI

Benign

0.19

PROVEAN

Benign

-1.4

N;N;N

Sift

Pathogenic

0.0

.;.;.

Sift4G

Pathogenic

0.0

.;.;.

Vest4

0.071

ClinPred

0.00081

GERP RS

-8.1

Mutation Taster

=97/3

polymorphism (auto)

(source)

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

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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