Genetic Variant PKD1L3:p.Ser1176Arg (chr16-71949873-G-C) – ACMG Classification: Benign (-12 pts)

Variant summary

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

The NM_181536.2(PKD1L3):c.3528C>G(p.Ser1176Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.354 in 1,551,090 control chromosomes in the GnomAD database, including 101,518 homozygotes. In-silico tool predicts a benign outcome for this variant. 8/12 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 0.33 ( 9180 hom., cov: 31)

Exomes 𝑓: 0.36 ( 92338 hom. )

Consequence

PKD1L3
NM_181536.2 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.61

Publications

24 publications found

Variant links:

Genes affected

PKD1L3 (HGNC:21716): (polycystin 1 like 3, transient receptor potential channel interacting) This gene encodes a member of the polycystin protein family. The encoded protein contains 11 transmembrane domains, a latrophilin/CL-1-like GPCR proteolytic site (GPS) domain, and a polycystin-1, lipoxygenase, alpha-toxin (PLAT) domain. This protein may function as a component of cation channel pores.[provided by RefSeq, Apr 2009]

PKD1L3 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=4.4823188E-5).

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.643 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PKD1L3	NM_181536.2 link	c.3528C>G	p.Ser1176Arg	missense_variant	Exon 21 of 30	ENST00000620267.2	NP_853514.1	Q7Z443

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PKD1L3	ENST00000620267.2 link	c.3528C>G	p.Ser1176Arg	missense_variant	Exon 21 of 30	1	NM_181536.2	ENSP00000480090.1		Q7Z443

Frequencies

GnomAD3 genomes

AF:

0.335

AC:

50835

AN:

151762

Hom.:

9179

Cov.:

show subpopulations

Gnomad AFR

AF:

0.261

Gnomad AMI

AF:

0.374

Gnomad AMR

AF:

0.450

Gnomad ASJ

AF:

0.309

Gnomad EAS

AF:

0.662

Gnomad SAS

AF:

0.310

Gnomad FIN

AF:

0.357

Gnomad MID

AF:

0.259

Gnomad NFE

AF:

0.329

Gnomad OTH

AF:

0.315

GnomAD2 exomes

AF:

0.388

AC:

60690

AN:

156544

AF XY:

0.379

show subpopulations

Gnomad AFR exome

AF:

0.262

Gnomad AMR exome

AF:

0.560

Gnomad ASJ exome

AF:

0.324

Gnomad EAS exome

AF:

0.674

Gnomad FIN exome

AF:

0.365

Gnomad NFE exome

AF:

0.327

Gnomad OTH exome

AF:

0.359

GnomAD4 exome

AF:

0.356

AC:

498718

AN:

1399212

Hom.:

92338

Cov.:

AF XY:

0.355

AC XY:

244673

AN XY:

690108

show subpopulations

African (AFR)

AF:

0.252

AC:

7964

AN:

31594

American (AMR)

AF:

0.544

AC:

19424

AN:

35704

Ashkenazi Jewish (ASJ)

AF:

0.323

AC:

8135

AN:

25182

East Asian (EAS)

AF:

0.615

AC:

21968

AN:

35738

South Asian (SAS)

AF:

0.314

AC:

24863

AN:

79226

European-Finnish (FIN)

AF:

0.364

AC:

17908

AN:

49260

Middle Eastern (MID)

AF:

0.241

AC:

1373

AN:

5688

European-Non Finnish (NFE)

AF:

0.348

AC:

375951

AN:

1078824

Other (OTH)

AF:

0.364

AC:

21132

AN:

57996

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.474

Heterozygous variant carriers

18561

37122

55684

74245

92806

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

12494

24988

37482

49976

62470

<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:

0.335

AC:

50852

AN:

151878

Hom.:

9180

Cov.:

AF XY:

0.338

AC XY:

25079

AN XY:

74216

show subpopulations

African (AFR)

AF:

0.261

AC:

10789

AN:

41394

American (AMR)

AF:

0.450

AC:

6864

AN:

15244

Ashkenazi Jewish (ASJ)

AF:

0.309

AC:

1074

AN:

3472

East Asian (EAS)

AF:

0.662

AC:

3410

AN:

5152

South Asian (SAS)

AF:

0.310

AC:

1493

AN:

4814

European-Finnish (FIN)

AF:

0.357

AC:

3763

AN:

10538

Middle Eastern (MID)

AF:

0.245

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.329

AC:

22387

AN:

67954

Other (OTH)

AF:

0.313

AC:

660

AN:

2106

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

1653

3305

4958

6610

8263

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

506

1012

1518

2024

2530

<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:

0.322

Hom.:

6121

Bravo

AF:

0.345

TwinsUK

AF:

0.352

AC:

1307

ALSPAC

AF:

0.340

AC:

1309

ESP6500AA

AF:

0.259

AC:

358

ESP6500EA

AF:

0.333

AC:

1060

ExAC

AF:

0.318

AC:

7574

Asia WGS

AF:

0.457

AC:

1588

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.96

BayesDel_addAF

Benign

-0.35

BayesDel_noAF

Benign

-0.14

CADD

Benign

(source)

DANN

Benign

0.81

DEOGEN2

Benign

0.35

FATHMM_MKL

Uncertain

0.78

LIST_S2

Benign

0.60

MetaRNN

Benign

0.000045

PhyloP100

1.6

PrimateAI

Benign

0.38

Sift4G

Uncertain

0.0060

Polyphen

1.0

Vest4

0.27

GERP RS

3.9

Varity_R

0.23

gMVP

0.70

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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