chr4-88056199-G-A

Variant names:

• chr4-88056199-G-A
• rs144968710
• NM_000297.4:c.1830G>A

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 0P and 17B. BP4_Strong BP6_Very_Strong BP7 BS1

The NM_000297.4(PKD2):​c.1830G>A​(p.Ala610Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000591 in 1,613,456 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00091 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00056 (1 hom.)
• Consequence: PKD2 NM_000297.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: -2.17
• Publications: 2 publications found

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: Labcorp Genetics (formerly Invitae), Ambry Genetics, Genomics England PanelApp

ACMG classification

Our verdict: Benign. The variant received -17 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.65).
• BP6: Variant 4-88056199-G-A is Benign according to our data. Variant chr4-88056199-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 255791.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-2.17 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.000906 (138/152254) while in subpopulation AFR AF = 0.00152 (63/41538). AF 95% confidence interval is 0.00122. There are 0 homozygotes in GnomAd4. There are 49 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PKD2	NM_000297.4	c.1830G>A	p.Ala610Ala	synonymous_variant	Exon 8 of 15	ENST00000237596.7	NP_000288.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PKD2	ENST00000237596.7	c.1830G>A	p.Ala610Ala	synonymous_variant	Exon 8 of 15	1	NM_000297.4	ENSP00000237596.2

Frequencies

GnomAD3 genomes AF: 0.000907 AC: 138 AN: 152136 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00155

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000851

Gnomad ASJ AF: 0.00403

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00124

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000559

Gnomad OTH AF: 0.000955

GnomAD2 exomes AF: 0.000868 AC: 218 AN: 251104 AF XY: 0.000884

Gnomad AFR exome AF: 0.00197

Gnomad AMR exome AF: 0.000752

Gnomad ASJ exome AF: 0.00437

Gnomad EAS exome AF: 0.000218

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000635

Gnomad OTH exome AF: 0.000816

GnomAD4 exome AF: 0.000558 AC: 816 AN: 1461202 Hom.: 1 Cov.: 30 AF XY: 0.000592 AC XY: 430 AN XY: 726962

African (AFR) AF: 0.00137 AC: 46 AN: 33462

American (AMR) AF: 0.000760 AC: 34 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00413 AC: 108 AN: 26124

East Asian (EAS) AF: 0.000126 AC: 5 AN: 39678

South Asian (SAS) AF: 0.00106 AC: 91 AN: 86246

European-Finnish (FIN) AF: 0.0000937 AC: 5 AN: 53372

Middle Eastern (MID) AF: 0.00243 AC: 14 AN: 5766

European-Non Finnish (NFE) AF: 0.000408 AC: 454 AN: 1111460

Other (OTH) AF: 0.000977 AC: 59 AN: 60370

GnomAD4 genome AF: 0.000906 AC: 138 AN: 152254 Hom.: 0 Cov.: 32 AF XY: 0.000658 AC XY: 49 AN XY: 74452

African (AFR) AF: 0.00152 AC: 63 AN: 41538

American (AMR) AF: 0.000850 AC: 13 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.00403 AC: 14 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.00124 AC: 6 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10590

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.000573 AC: 39 AN: 68022

Other (OTH) AF: 0.000945 AC: 2 AN: 2116

Alfa AF: 0.000899 Hom.: 0

Bravo AF: 0.000990

Asia WGS AF: 0.00115 AC: 4 AN: 3478

EpiCase AF: 0.000981

EpiControl AF: 0.000948

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:4

Feb 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PKD2: BP4, BP7 -

-

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Sep 23, 2021

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 24658975) -

not specified Benign:3

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jan 21, 2021

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Polycystic kidney disease 2 Benign:2

Apr 28, 2017

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Dec 27, 2019

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Polycystic kidney disease Benign:1

-

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

The PKD2 p.Ala610Ala variant was identified in dbSNP (ID: rs144968710) as “N/A”, ADPKD Mutation Database (likely neutral), 1000 Genomes Project in 8 of 5000 chromosomes (frequency: 0.002), NHLBI GO Exome Sequencing Project in 8 of 8600 European American and in 10 of 4406 African American alleles, the Exome Aggregation Consortium database (August 8, 2016) in 94 of 121226 chromosomes (freq. 0.0008) in the following populations: European in 39 of 66662 chromosomes (freq. 0.0006), African in 19 of 10406 chromosomes (freq. 0.002), South Asian in 19 of 16482 chromosomes (freq. 0.001), Latino in 12 of 11560 chromosomes (freq. 0.001), Finish in 3 of 6600 chromosomes (freq. 0.0005), Other 2 in 906 chromosomes (freq. 0.002), increasing the likelihood this could be a low frequency benign variant. The p.Ala610Ala variant is not expected to have clinical significance because it does not result in a change of amino acid and is not located in a known consensus splice site. The variant occurs outside of the splicing consensus sequence and 3 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict a greater than 10% difference in splicing. However, this information is not predictive enough to assume pathogenicity. In summary, based on the above information, the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign. -

Autosomal dominant polycystic kidney disease Benign:1

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.65
CADD	Benign	0.88
DANN	Benign	0.58
PhyloP100		-2.2
PromoterAI		-0.038	Neutral
Mutation Taster		=97/3	polymorphism

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

Other links and lift over

dbSNP: rs144968710; hg19: chr4-88977351;