Genetic Variant PKD2L1:p.Ala788Asp (chr10-100288451-G-T) – ACMG Classification: Benign (-12 pts)

Variant summary

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

The NM_016112.3(PKD2L1):c.2363C>A(p.Ala788Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0511 in 1,609,924 control chromosomes in the GnomAD database, including 2,372 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 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 0.062 ( 337 hom., cov: 32)

Exomes 𝑓: 0.050 ( 2035 hom. )

Consequence

PKD2L1
NM_016112.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.574

Publications

20 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 -12 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0016729236).

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0925 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_016112.3. 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
	PKD2L1	NM_016112.3	MANE Select	c.2363C>A	p.Ala788Asp	missense	Exon 16 of 16	NP_057196.2
	PKD2L1	NM_001253837.2		c.2222C>A	p.Ala741Asp	missense	Exon 16 of 16	NP_001240766.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
PKD2L1	ENST00000318222.4	TSL:1 MANE Select	c.2363C>A	p.Ala788Asp	missense	Exon 16 of 16	ENSP00000325296.3	Q9P0L9-1
PKD2L1	ENST00000528248.1	TSL:1	n.*2103C>A		non_coding_transcript_exon	Exon 16 of 16	ENSP00000436514.1	H0YET4
PKD2L1	ENST00000528248.1	TSL:1	n.*2103C>A		3_prime_UTR	Exon 16 of 16	ENSP00000436514.1	H0YET4

Frequencies

GnomAD3 genomes

AF:

0.0624

AC:

9489

AN:

152050

Hom.:

337

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0952

Gnomad AMI

AF:

0.0738

Gnomad AMR

AF:

0.0493

Gnomad ASJ

AF:

0.0565

Gnomad EAS

AF:

0.0557

Gnomad SAS

AF:

0.0646

Gnomad FIN

AF:

0.0556

Gnomad MID

AF:

0.0316

Gnomad NFE

AF:

0.0470

Gnomad OTH

AF:

0.0665

GnomAD2 exomes

AF:

0.0516

AC:

12947

AN:

251146

AF XY:

0.0509

show subpopulations

Gnomad AFR exome

AF:

0.0982

Gnomad AMR exome

AF:

0.0450

Gnomad ASJ exome

AF:

0.0559

Gnomad EAS exome

AF:

0.0523

Gnomad FIN exome

AF:

0.0496

Gnomad NFE exome

AF:

0.0441

Gnomad OTH exome

AF:

0.0502

GnomAD4 exome

AF:

0.0499

AC:

72748

AN:

1457756

Hom.:

2035

Cov.:

AF XY:

0.0498

AC XY:

36114

AN XY:

725462

show subpopulations

African (AFR)

AF:

0.0960

AC:

3200

AN:

33350

American (AMR)

AF:

0.0456

AC:

2037

AN:

44716

Ashkenazi Jewish (ASJ)

AF:

0.0544

AC:

1422

AN:

26118

East Asian (EAS)

AF:

0.0645

AC:

2560

AN:

39672

South Asian (SAS)

AF:

0.0576

AC:

4966

AN:

86162

European-Finnish (FIN)

AF:

0.0517

AC:

2761

AN:

53406

Middle Eastern (MID)

AF:

0.0485

AC:

279

AN:

5758

European-Non Finnish (NFE)

AF:

0.0470

AC:

52083

AN:

1108342

Other (OTH)

AF:

0.0571

AC:

3440

AN:

60232

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.444

Heterozygous variant carriers

3115

6230

9344

12459

15574

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

2074

4148

6222

8296

10370

<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:

0.0624

AC:

9496

AN:

152168

Hom.:

337

Cov.:

AF XY:

0.0627

AC XY:

4662

AN XY:

74408

show subpopulations

African (AFR)

AF:

0.0950

AC:

3942

AN:

41488

American (AMR)

AF:

0.0493

AC:

754

AN:

15288

Ashkenazi Jewish (ASJ)

AF:

0.0565

AC:

196

AN:

3470

East Asian (EAS)

AF:

0.0560

AC:

290

AN:

5174

South Asian (SAS)

AF:

0.0645

AC:

311

AN:

4822

European-Finnish (FIN)

AF:

0.0556

AC:

589

AN:

10596

Middle Eastern (MID)

AF:

0.0340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0470

AC:

3198

AN:

68016

Other (OTH)

AF:

0.0658

AC:

139

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

441

881

1322

1762

2203

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

112

224

336

448

560

<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:

0.0502

Hom.:

516

Bravo

AF:

0.0634

TwinsUK

AF:

0.0450

AC:

167

ALSPAC

AF:

0.0472

AC:

182

ESP6500AA

AF:

0.0940

AC:

414

ESP6500EA

AF:

0.0462

AC:

397

ExAC

AF:

0.0524

AC:

6364

EpiCase

AF:

0.0440

EpiControl

AF:

0.0436

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.079

BayesDel_addAF

Benign

-0.54

BayesDel_noAF

Benign

-0.48

CADD

Benign

5.4

(source)

DANN

Benign

0.68

DEOGEN2

Benign

0.014

Eigen

Benign

-0.78

Eigen_PC

Benign

-0.93

FATHMM_MKL

Benign

0.031

LIST_S2

Benign

0.35

MetaRNN

Benign

0.0017

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.55

PhyloP100

-0.57

PrimateAI

Benign

0.28

PROVEAN

Benign

-0.68

REVEL

Benign

0.14

Sift

Pathogenic

0.0

Sift4G

Benign

0.23

Polyphen

0.0010

Vest4

0.038

MPC

0.33

ClinPred

0.075

GERP RS

-1.1

Varity_R

0.26

gMVP

0.44

Mutation Taster

=96/4

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over