4-88008021-CGAGGAGGAG-CGAGGAGGAGGAG

Variant names:

• chr4-88008021-C-CGAG
• rs750077647
• NM_000297.4:c.305_307dupAGG

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 0P and 17B. BP3 BP6_Very_Strong BS1 BS2

The NM_000297.4(PKD2):​c.305_307dupAGG​(p.Glu102dup) variant causes a disruptive inframe insertion change. The variant allele was found at a frequency of 0.00112 in 1,516,764 control chromosomes in the GnomAD database, including 11 homozygotes. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0046 (9 hom., cov: 32)
  • Exomes 𝑓: 0.00073 (2 hom.)
• Consequence: PKD2 NM_000297.4 disruptive_inframe_insertion
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: 4.02
• Publications: 3 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

ENSG00000286618 (HGNC:):

ACMG classification

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

• BP3: Nonframeshift variant in repetitive region in NM_000297.4
• BP6: Variant 4-88008021-C-CGAG is Benign according to our data. Variant chr4-88008021-C-CGAG is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 193079.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00463 (698/150616) while in subpopulation AFR AF = 0.0148 (611/41376). AF 95% confidence interval is 0.0138. There are 9 homozygotes in GnomAd4. There are 351 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 9 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PKD2	NM_000297.4	MANE Select	c.305_307dupAGG	p.Glu102dup	disruptive_inframe_insertion	Exon 1 of 15	NP_000288.1	Q13563-1
	PKD2	NM_001440544.1		c.305_307dupAGG	p.Glu102dup	disruptive_inframe_insertion	Exon 1 of 14	NP_001427473.1
	PKD2	NR_156488.2		n.404_406dupAGG		non_coding_transcript_exon	Exon 1 of 14

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PKD2	ENST00000237596.7	TSL:1 MANE Select	c.305_307dupAGG	p.Glu102dup	disruptive_inframe_insertion	Exon 1 of 15	ENSP00000237596.2	Q13563-1
	PKD2	ENST00000927447.1		c.305_307dupAGG	p.Glu102dup	disruptive_inframe_insertion	Exon 1 of 15	ENSP00000597506.1
	PKD2	ENST00000927448.1		c.305_307dupAGG	p.Glu102dup	disruptive_inframe_insertion	Exon 1 of 14	ENSP00000597507.1

Frequencies

GnomAD3 genomes AF: 0.00462 AC: 696 AN: 150526 Hom.: 9 Cov.: 32

Gnomad AFR AF: 0.0148

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00324

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00955

Gnomad NFE AF: 0.000341

Gnomad OTH AF: 0.00580

GnomAD2 exomes AF: 0.00146 AC: 143 AN: 97700 AF XY: 0.00105

Gnomad AFR exome AF: 0.0198

Gnomad AMR exome AF: 0.00174

Gnomad ASJ exome AF: 0.000149

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000608

Gnomad OTH exome AF: 0.00366

GnomAD4 exome AF: 0.000729 AC: 996 AN: 1366148 Hom.: 2 Cov.: 34 AF XY: 0.000642 AC XY: 433 AN XY: 673950

African (AFR) AF: 0.0161 AC: 487 AN: 30168

American (AMR) AF: 0.00203 AC: 69 AN: 33916

Ashkenazi Jewish (ASJ) AF: 0.0000405 AC: 1 AN: 24712

East Asian (EAS) AF: 0.00 AC: 0 AN: 34468

South Asian (SAS) AF: 0.000117 AC: 9 AN: 77214

European-Finnish (FIN) AF: 0.0000297 AC: 1 AN: 33702

Middle Eastern (MID) AF: 0.00624 AC: 35 AN: 5610

European-Non Finnish (NFE) AF: 0.000248 AC: 265 AN: 1069210

Other (OTH) AF: 0.00226 AC: 129 AN: 57148

GnomAD4 genome AF: 0.00463 AC: 698 AN: 150616 Hom.: 9 Cov.: 32 AF XY: 0.00477 AC XY: 351 AN XY: 73562

African (AFR) AF: 0.0148 AC: 611 AN: 41376

American (AMR) AF: 0.00323 AC: 49 AN: 15148

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3442

East Asian (EAS) AF: 0.00 AC: 0 AN: 5134

South Asian (SAS) AF: 0.00 AC: 0 AN: 4818

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10006

Middle Eastern (MID) AF: 0.0103 AC: 3 AN: 292

European-Non Finnish (NFE) AF: 0.000341 AC: 23 AN: 67398

Other (OTH) AF: 0.00574 AC: 12 AN: 2090

Alfa AF: 0.000261 Hom.: 1

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (4)
-	-	3	not provided (3)
-	-	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
PhyloP100		4.0
Mutation Taster		=75/25	polymorphism

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs750077647; hg19: chr4-88929173; COSMIC: COSV52936189; COSMIC: COSV52936189;