chr4-88046767-T-G

Position:

• chr4-88046767-T-G

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_000297.4(PKD2):​c.1445T>G​(p.Phe482Cys) variant causes a missense change. The variant allele was found at a frequency of 0.00218 in 1,611,890 control chromosomes in the GnomAD database, including 13 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0018 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0022 (12 hom.)
• Consequence: PKD2 NM_000297.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:11
• Conservation: PhyloP100: 6.08

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]

ACMG classification

Verdict is Benign. Variant got -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.013403147).
• BP6: Variant 4-88046767-T-G is Benign according to our data. Variant chr4-88046767-T-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 219481.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Benign=5, Uncertain_significance=1}. Variant chr4-88046767-T-G is described in Lovd as [Likely_benign]. Variant chr4-88046767-T-G is described in Lovd as [Pathogenic]. Variant chr4-88046767-T-G is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.00184 (281/152356) while in subpopulation AMR AF= 0.00255 (39/15304). AF 95% confidence interval is 0.00208. There are 1 homozygotes in gnomad4. There are 127 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 281 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PKD2	NM_000297.4	c.1445T>G	p.Phe482Cys	missense_variant	6/15	ENST00000237596.7	NP_000288.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PKD2	ENST00000237596.7	c.1445T>G	p.Phe482Cys	missense_variant	6/15	1	NM_000297.4	ENSP00000237596	P1
PKD2	ENST00000508588.5	c.-199+3310T>G		intron_variant		2		ENSP00000427131

Frequencies

GnomAD3 genomes AF: 0.00185 AC: 282 AN: 152238 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000507

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00255

Gnomad ASJ AF: 0.00951

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00145

Gnomad FIN AF: 0.000188

Gnomad MID AF: 0.0190

Gnomad NFE AF: 0.00238

Gnomad OTH AF: 0.00574

GnomAD3 exomes AF: 0.00204 AC: 513 AN: 251372 Hom.: 3 AF XY: 0.00202 AC XY: 275 AN XY: 135850

Gnomad AFR exome AF: 0.000246

Gnomad AMR exome AF: 0.00194

Gnomad ASJ exome AF: 0.00972

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000980

Gnomad FIN exome AF: 0.0000924

Gnomad NFE exome AF: 0.00246

Gnomad OTH exome AF: 0.00522

GnomAD4 exome AF: 0.00221 AC: 3225 AN: 1459534 Hom.: 12 Cov.: 29 AF XY: 0.00221 AC XY: 1606 AN XY: 726232

Gnomad4 AFR exome AF: 0.000658

Gnomad4 AMR exome AF: 0.00195

Gnomad4 ASJ exome AF: 0.00950

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00122

Gnomad4 FIN exome AF: 0.000168

Gnomad4 NFE exome AF: 0.00213

Gnomad4 OTH exome AF: 0.00343

GnomAD4 genome AF: 0.00184 AC: 281 AN: 152356 Hom.: 1 Cov.: 32 AF XY: 0.00170 AC XY: 127 AN XY: 74498

Gnomad4 AFR AF: 0.000505

Gnomad4 AMR AF: 0.00255

Gnomad4 ASJ AF: 0.00951

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00145

Gnomad4 FIN AF: 0.000188

Gnomad4 NFE AF: 0.00238

Gnomad4 OTH AF: 0.00568

Alfa AF: 0.00267 Hom.: 8

Bravo AF: 0.00202

TwinsUK AF: 0.00189 AC: 7

ALSPAC AF: 0.00182 AC: 7

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00349 AC: 30

ExAC AF: 0.00212 AC: 257

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00365

EpiControl AF: 0.00362

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:11

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Benign:6

Likely benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jun 05, 2018	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2023	PKD2: PM5, BP4, BS1, BS2 -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 15, 2021	This variant is associated with the following publications: (PMID: 32859249, 18257781, 27894351, 27884173, 18837007, 22995991, 22863349, 31349084) -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -

Polycystic kidney disease 2 Uncertain:1 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	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). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	May 07, 2020	- -

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Aug 03, 2015	- -
Likely benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

Polycystic kidney disease Benign:1

Likely benign, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

-

The PKD2 p.Phe482Cys variant was identified in 7 of 954 proband chromosomes (frequency: 0.01) from individuals or families with ADPKD (Bataille 2011, Dedoussis 2008, Edrees 2016, Robinson 2012, Rossetti 2012, Tan 2008). The variant was also identified in the following databases: dbSNP (ID: rs75762896) as With other allele, ClinVar (classified as benign by Invitae; as likely benign by Prevention), Clinvitae , LOVD 3.0, ADPKD Mutation Database (classified as likely neutral). The variant was not identified in the COGR, or PKD1-LOVD databases. The variant was identified in control databases in 548 of 277128 chromosomes (3 homozygous) at a frequency of 0.002 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). Observations by population include African in 7 of 24034 chromosomes (freq: 0.0003), “Other” in 38 of 6462 chromosomes (freq: 0.01), Latino in 67 of 34416 chromosomes (freq: 0.002), EuropeanNon-Finnish in 302 of 126624 chromosomes (freq: 0.002), AshkenaziJewish in 102 of 10152 chromosomes (freq: 0.01), EuropeanFinnish in 3 of 25792 chromosomes (freq: 0.0001), and SouthAsian in 29 of 30782 chromosomes (freq: 0.001); it was not observed in the EastAsian population. The p.Phe482 residue is conserved in mammals but not in more distantly related organisms, and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the variant may impact the protein; however, this information is not predictive enough to assume pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. The variant was identified with a co-occurring pathogenic PKD1 variant (IVS21–2delAG), increasing the likelihood that the p.Phe482Cys variant does not have clinical significance (Dedoussis 2008). 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

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 29, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.088
BayesDel_addAF	Benign	-0.30	T
BayesDel_noAF	Benign	-0.21
CADD	Pathogenic	26
DANN	Uncertain	0.99
DEOGEN2	Benign	0.28	T
Eigen	Uncertain	0.34
Eigen_PC	Uncertain	0.45
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Benign	0.80	T
M_CAP	Uncertain	0.17	D
MetaRNN	Benign	0.013	T
MetaSVM	Benign	-0.36	T
MutationAssessor	Benign	1.4	L
MutationTaster	Benign	0.94	D;D
PrimateAI	Benign	0.43	T
PROVEAN	Benign	-1.3	N
REVEL	Benign	0.18
Sift	Uncertain	0.0050	D
Sift4G	Uncertain	0.012	D
Polyphen		0.52	P
Vest4		0.37
MVP		0.28
MPC		0.63
ClinPred		0.031	T
GERP RS		5.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.8
Varity_R		0.23
gMVP		0.80

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs75762896; hg19: chr4-88967919;