4-88052059-G-C

Variant names:

• chr4-88052059-G-C
• rs145297759
• NM_000297.4:c.1617G>C

Variant summary

Our verdict is Benign. The variant received -15 ACMG points: 0P and 15B. BP4_Moderate BP6_Very_Strong BP7 BS1

The NM_000297.4(PKD2):​c.1617G>C​(p.Leu539Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000323 in 1,602,076 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. L539L) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0018 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00016 (1 hom.)
• Consequence: PKD2 NM_000297.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -0.0250
• Publications: 0 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: ClinGen, Orphanet
• polycystic kidney disease 2

  Inheritance: AD, AR Classification: STRONG, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp, Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -15 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.45).
• BP6: Variant 4-88052059-G-C is Benign according to our data. Variant chr4-88052059-G-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 543950.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.025 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00183 (279/152176) while in subpopulation AFR AF = 0.00633 (263/41518). AF 95% confidence interval is 0.00571. There are 1 homozygotes in GnomAd4. There are 131 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PKD2	NM_000297.4	MANE Select	c.1617G>C	p.Leu539Leu	synonymous	Exon 7 of 15	NP_000288.1	Q13563-1
	PKD2	NM_001440544.1		c.1392G>C	p.Leu464Leu	synonymous	Exon 6 of 14	NP_001427473.1
	PKD2	NR_156488.2		n.1716G>C		non_coding_transcript_exon	Exon 7 of 14

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PKD2	ENST00000237596.7	TSL:1 MANE Select	c.1617G>C	p.Leu539Leu	synonymous	Exon 7 of 15	ENSP00000237596.2	Q13563-1
	PKD2	ENST00000927447.1		c.1617G>C	p.Leu539Leu	synonymous	Exon 7 of 15	ENSP00000597506.1
	PKD2	ENST00000927448.1		c.1617G>C	p.Leu539Leu	synonymous	Exon 7 of 14	ENSP00000597507.1

Frequencies

GnomAD3 genomes AF: 0.00182 AC: 277 AN: 152058 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.00630

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000655

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: 0.00

Gnomad OTH AF: 0.00287

GnomAD2 exomes AF: 0.000438 AC: 110 AN: 251150 AF XY: 0.000317

Gnomad AFR exome AF: 0.00609

Gnomad AMR exome AF: 0.000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.000165 AC: 239 AN: 1449900 Hom.: 1 Cov.: 27 AF XY: 0.000148 AC XY: 107 AN XY: 722166

African (AFR) AF: 0.00602 AC: 200 AN: 33236

American (AMR) AF: 0.000313 AC: 14 AN: 44692

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26066

East Asian (EAS) AF: 0.00 AC: 0 AN: 39598

South Asian (SAS) AF: 0.00 AC: 0 AN: 85942

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53394

Middle Eastern (MID) AF: 0.000174 AC: 1 AN: 5750

European-Non Finnish (NFE) AF: 9.08e-7 AC: 1 AN: 1101260

Other (OTH) AF: 0.000384 AC: 23 AN: 59962

GnomAD4 genome AF: 0.00183 AC: 279 AN: 152176 Hom.: 1 Cov.: 32 AF XY: 0.00176 AC XY: 131 AN XY: 74406

African (AFR) AF: 0.00633 AC: 263 AN: 41518

American (AMR) AF: 0.000654 AC: 10 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5176

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10592

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67982

Other (OTH) AF: 0.00284 AC: 6 AN: 2112

Alfa AF: 0.0000839 Hom.: 0

Bravo AF: 0.00231

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	2	Polycystic kidney disease 2 (2)
-	-	1	Autosomal dominant polycystic kidney disease (1)
-	-	1	PKD2-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.45
CADD	Benign	2.6
DANN	Benign	0.67
PhyloP100		-0.025
Mutation Taster		=296/4	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: rs145297759; hg19: chr4-88973211;