NM_000297.4:c.302_307dupAGGAGG

Variant names:

• chr4-88008021-C-CGAGGAG
• rs750077647
• NM_000297.4:c.302_307dupAGGAGG

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP3

The NM_000297.4(PKD2):​c.302_307dupAGGAGG​(p.Glu101_Glu102dup) variant causes a disruptive inframe insertion change. The variant allele was found at a frequency of 0.00000366 in 1,366,212 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000037 (0 hom.)
• Consequence: PKD2 NM_000297.4 disruptive_inframe_insertion
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• 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: Orphanet, ClinGen
• polycystic kidney disease 2

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

ENSG00000286618 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP3: Nonframeshift variant in repetitive region in NM_000297.4

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PKD2	NM_000297.4	MANE Select	c.302_307dupAGGAGG	p.Glu101_Glu102dup	disruptive_inframe_insertion	Exon 1 of 15	NP_000288.1
	PKD2	NM_001440544.1		c.302_307dupAGGAGG	p.Glu101_Glu102dup	disruptive_inframe_insertion	Exon 1 of 14	NP_001427473.1
	PKD2	NR_156488.2		n.401_406dupAGGAGG		non_coding_transcript_exon	Exon 1 of 14

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PKD2	ENST00000237596.7	TSL:1 MANE Select	c.302_307dupAGGAGG	p.Glu101_Glu102dup	disruptive_inframe_insertion	Exon 1 of 15	ENSP00000237596.2
	ENSG00000286618	ENST00000662475.1		n.112+339_112+344dupCTCCTC		intron	N/A
	PKD2	ENST00000506727.1	TSL:4	n.-211_-210insGAGGAG		upstream_gene	N/A

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000366 AC: 5 AN: 1366212 Hom.: 0 Cov.: 34 AF XY: 0.00000593 AC XY: 4 AN XY: 673984

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 30178

American (AMR) AF: 0.00 AC: 0 AN: 33920

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24712

East Asian (EAS) AF: 0.0000870 AC: 3 AN: 34474

South Asian (SAS) AF: 0.00 AC: 0 AN: 77214

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 33704

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5610

European-Non Finnish (NFE) AF: 0.00000187 AC: 2 AN: 1069250

Other (OTH) AF: 0.00 AC: 0 AN: 57150

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.00000000000315292), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Polycystic kidney disease 2 Uncertain:1

Feb 15, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		4.0

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;