Genetic Variant PKD2:p.Ala190Ala (chr4-88008303-G-T) – ACMG Classification: Benign (-21 pts)

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2

The NM_000297.4(PKD2):c.570G>T(p.Ala190Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000977 in 1,511,642 control chromosomes in the GnomAD database, including 16 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0052 ( 4 hom., cov: 32)

Exomes 𝑓: 0.00051 ( 12 hom. )

Consequence

PKD2
NM_000297.4 synonymous

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9

Conservation

PhyloP100: -0.0680

Publications

1 publications found

Variant links:

Genes affected

PKD2 (HGNC:9009): (polycystin 2, transient receptor potential cation channel) This gene encodes a member of the polycystin protein family. The encoded protein is a multi-pass membrane protein that functions as a calcium permeable cation channel, and is involved in calcium transport and calcium signaling in renal epithelial cells. This protein interacts with polycystin 1, and they may be partners in a common signaling cascade involved in tubular morphogenesis. Mutations in this gene are associated with autosomal dominant polycystic kidney disease type 2. [provided by RefSeq, Mar 2011]

PKD2 Gene-Disease associations (from GenCC):

autosomal dominant polycystic kidney disease
Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, ClinGen
polycystic kidney disease 2
Inheritance: AD, AR Classification: STRONG, LIMITED Submitted by: Genomics England PanelApp, Ambry Genetics, Labcorp Genetics (formerly Invitae)

PKD2 links:

ENSG00000286618 (HGNC:):

ENSG00000286618 links:

Genome browser will be placed here

new If you want to explore the variant's impact on the transcript NM_000297.4, check out the Mutation Effect Viewer. This is especially useful for frameshift variants or if you want to visualize the effect of exon loss / intron retention.

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.56).

BP6

Variant 4-88008303-G-T is Benign according to our data. Variant chr4-88008303-G-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 255795.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-0.068 with no splicing effect.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00516 (786/152184) while in subpopulation AFR AF = 0.0179 (743/41558). AF 95% confidence interval is 0.0168. There are 4 homozygotes in GnomAd4. There are 361 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 4 AD,AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000297.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
PKD2	NM_000297.4	MANE Select	c.570G>T	p.Ala190Ala	synonymous	Exon 1 of 15	NP_000288.1	Q13563-1
PKD2	NM_001440544.1		c.570G>T	p.Ala190Ala	synonymous	Exon 1 of 14	NP_001427473.1
PKD2	NR_156488.2		n.669G>T		non_coding_transcript_exon	Exon 1 of 14

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
PKD2	ENST00000237596.7	TSL:1 MANE Select	c.570G>T	p.Ala190Ala	synonymous	Exon 1 of 15	ENSP00000237596.2	Q13563-1
PKD2	ENST00000927447.1		c.570G>T	p.Ala190Ala	synonymous	Exon 1 of 15	ENSP00000597506.1
PKD2	ENST00000927448.1		c.570G>T	p.Ala190Ala	synonymous	Exon 1 of 14	ENSP00000597507.1

Frequencies

GnomAD3 genomes

AF:

0.00514

AC:

781

AN:

152072

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0178

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00196

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000441

Gnomad OTH

AF:

0.00478

GnomAD2 exomes

AF:

0.000850

AC:

AN:

109366

AF XY:

0.000628

show subpopulations

Gnomad AFR exome

AF:

0.0230

Gnomad AMR exome

AF:

0.000843

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000247

Gnomad OTH exome

AF:

0.000301

GnomAD4 exome

AF:

0.000508

AC:

691

AN:

1359458

Hom.:

Cov.:

AF XY:

0.000436

AC XY:

292

AN XY:

670426

show subpopulations

African (AFR)

AF:

0.0199

AC:

575

AN:

28884

American (AMR)

AF:

0.000926

AC:

AN:

33492

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24548

East Asian (EAS)

AF:

0.00

AC:

AN:

33760

South Asian (SAS)

AF:

0.0000261

AC:

AN:

76484

European-Finnish (FIN)

AF:

0.00

AC:

AN:

33260

Middle Eastern (MID)

AF:

0.000250

AC:

AN:

4000

European-Non Finnish (NFE)

AF:

0.0000356

AC:

AN:

1068326

Other (OTH)

AF:

0.000776

AC:

AN:

56704

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.491

Heterozygous variant carriers

104

139

174

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

100

<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:

0.00516

AC:

786

AN:

152184

Hom.:

Cov.:

AF XY:

0.00485

AC XY:

361

AN XY:

74398

show subpopulations

African (AFR)

AF:

0.0179

AC:

743

AN:

41558

American (AMR)

AF:

0.00196

AC:

AN:

15300

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5126

South Asian (SAS)

AF:

0.00

AC:

AN:

4834

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10610

Middle Eastern (MID)

AF:

0.00

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.0000441

AC:

AN:

67966

Other (OTH)

AF:

0.00473

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

122

162

203

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<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:

0.000729

Hom.:

Bravo

AF:

0.00607

ClinVar

ClinVar submissions

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (4)

Polycystic kidney disease 2 (3)

Autosomal dominant polycystic kidney disease (1)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.56

CADD

Benign

(source)

DANN

Benign

0.91

PhyloP100

-0.068

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

Mutation Taster

=100/0

polymorphism

(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

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

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