rs117078377

Positions:

• chr4-88008301-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000297.4(PKD2):​c.568G>A​(p.Ala190Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0258 in 1,511,924 control chromosomes in the GnomAD database, including 3,051 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. A190A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.030 (429 hom., cov: 32)
  • Exomes 𝑓: 0.025 (2622 hom.)
• Consequence: PKD2 NM_000297.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 1.51

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]

(HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.002696067).
• BP6: Variant 4-88008301-G-A is Benign according to our data. Variant chr4-88008301-G-A is described in ClinVar as [Benign]. Clinvar id is 92796.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-88008301-G-A is described in Lovd as [Benign]. Variant chr4-88008301-G-A is described in Lovd as [Likely_benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.369 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PKD2	NM_000297.4	c.568G>A	p.Ala190Thr	missense_variant	1/15	ENST00000237596.7	NP_000288.1
PKD2	XM_011532028.3	c.568G>A	p.Ala190Thr	missense_variant	1/14		XP_011530330.1
PKD2	NR_156488.2	n.667G>A		non_coding_transcript_exon_variant	1/14

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PKD2	ENST00000237596.7	c.568G>A	p.Ala190Thr	missense_variant	1/15	1	NM_000297.4	ENSP00000237596	P1
	ENST00000662475.1	n.112+65C>T		intron_variant, non_coding_transcript_variant
PKD2	ENST00000506727.1	n.70G>A		non_coding_transcript_exon_variant	1/4	4

Frequencies

GnomAD3 genomes AF: 0.0298 AC: 4535 AN: 152046 Hom.: 434 Cov.: 32

Gnomad AFR AF: 0.00432

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0220

Gnomad ASJ AF: 0.0328

Gnomad EAS AF: 0.384

Gnomad SAS AF: 0.0842

Gnomad FIN AF: 0.0636

Gnomad MID AF: 0.00955

Gnomad NFE AF: 0.0117

Gnomad OTH AF: 0.0315

GnomAD3 exomes AF: 0.0631 AC: 6927 AN: 109856 Hom.: 946 AF XY: 0.0638 AC XY: 3878 AN XY: 60784

Gnomad AFR exome AF: 0.00280

Gnomad AMR exome AF: 0.0246

Gnomad ASJ exome AF: 0.0367

Gnomad EAS exome AF: 0.438

Gnomad SAS exome AF: 0.0725

Gnomad FIN exome AF: 0.0596

Gnomad NFE exome AF: 0.0128

Gnomad OTH exome AF: 0.0413

GnomAD4 exome AF: 0.0254 AC: 34475 AN: 1359764 Hom.: 2622 Cov.: 35 AF XY: 0.0268 AC XY: 17982 AN XY: 670572

Gnomad4 AFR exome AF: 0.00294

Gnomad4 AMR exome AF: 0.0247

Gnomad4 ASJ exome AF: 0.0349

Gnomad4 EAS exome AF: 0.331

Gnomad4 SAS exome AF: 0.0727

Gnomad4 FIN exome AF: 0.0633

Gnomad4 NFE exome AF: 0.0107

Gnomad4 OTH exome AF: 0.0404

GnomAD4 genome AF: 0.0297 AC: 4525 AN: 152160 Hom.: 429 Cov.: 32 AF XY: 0.0349 AC XY: 2593 AN XY: 74388

Gnomad4 AFR AF: 0.00431

Gnomad4 AMR AF: 0.0220

Gnomad4 ASJ AF: 0.0328

Gnomad4 EAS AF: 0.383

Gnomad4 SAS AF: 0.0839

Gnomad4 FIN AF: 0.0636

Gnomad4 NFE AF: 0.0117

Gnomad4 OTH AF: 0.0326

Alfa AF: 0.0188 Hom.: 27

Bravo AF: 0.0279

TwinsUK AF: 0.0108 AC: 40

ALSPAC AF: 0.0135 AC: 52

ExAC AF: 0.0351 AC: 833

Asia WGS AF: 0.202 AC: 701 AN: 3472

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jun 23, 2016	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 12, 2018	This variant is associated with the following publications: (PMID: 17574468, 22008521, 22863349, 18837007, 11438989, 20981092, 15192819, 27894351) -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Polycystic kidney disease 2 Benign:2

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Dec 27, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Mar 06, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Polycystic kidney disease Benign:1

Benign, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

-

The c.568G>A, p.Ala190Thr variant was identified in 6.32% of 645 control alleles in the Exome Aggregation Consortium (March 14, 2016). According to ACMG guidelines for variant classification based on allele frequency, category BA1, this variant is considered benign and has not been further reviewed (Richards 2015). -

Autosomal dominant polycystic kidney disease Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.40	T
BayesDel_noAF	Benign	-0.21
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.31	T
Eigen	Benign	0.13
Eigen_PC	Benign	0.18
FATHMM_MKL	Benign	0.42	N
LIST_S2	Benign	0.68	T
MetaRNN	Benign	0.0027	T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	0.90	L
MutationTaster	Benign	0.014	P
PrimateAI	Pathogenic	0.86	D
PROVEAN	Benign	-0.57	N
REVEL	Benign	0.12
Sift	Benign	0.43	T
Sift4G	Benign	0.41	T
Polyphen		0.91	P
Vest4		0.056
MPC		0.30
ClinPred		0.050	T
GERP RS		4.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.16
gMVP		0.32

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

LitVar

Other links and lift over

dbSNP: rs117078377; hg19: chr4-88929453; COSMIC: COSV52939069;