rs1474473957

Variant names:

• chr4-88007773-GA-G
• rs1474473957
• NM_000297.4:c.41delA

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PVS1 PM2 PP5

The NM_000297.4(PKD2):​c.41delA​(p.Asp14AlafsTer16) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000972 in 1,029,044 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. D14D) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 9.7e-7 (0 hom.)
• Consequence: PKD2 NM_000297.4 frameshift
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:2
• Conservation: PhyloP100: 0.306
• 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: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Ambry Genetics

ENSG00000286618 (HGNC:):

ACMG classification

Our verdict: Pathogenic. The variant received 11 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. There are 360 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 4-88007773-GA-G is Pathogenic according to our data. Variant chr4-88007773-GA-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 1344891.

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.41delA	p.Asp14AlafsTer16	frameshift	Exon 1 of 15	NP_000288.1	Q13563-1
	PKD2	NM_001440544.1		c.41delA	p.Asp14AlafsTer16	frameshift	Exon 1 of 14	NP_001427473.1
	PKD2	NR_156488.2		n.140delA		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.41delA	p.Asp14AlafsTer16	frameshift	Exon 1 of 15	ENSP00000237596.2	Q13563-1
	PKD2	ENST00000927447.1		c.41delA	p.Asp14AlafsTer16	frameshift	Exon 1 of 15	ENSP00000597506.1
	PKD2	ENST00000927448.1		c.41delA	p.Asp14AlafsTer16	frameshift	Exon 1 of 14	ENSP00000597507.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 9.72e-7 AC: 1 AN: 1029044 Hom.: 0 Cov.: 28 AF XY: 0.00000201 AC XY: 1 AN XY: 496502

African (AFR) AF: 0.0000501 AC: 1 AN: 19964

American (AMR) AF: 0.00 AC: 0 AN: 12506

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 13352

East Asian (EAS) AF: 0.00 AC: 0 AN: 14214

South Asian (SAS) AF: 0.00 AC: 0 AN: 34560

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 15626

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2644

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 878488

Other (OTH) AF: 0.00 AC: 0 AN: 37690

GnomAD4 genome Cov.: 33

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.00000756

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
1	1	-	Polycystic kidney disease 2 (2)
-	1	-	PKD2-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.31
Mutation Taster		=3/197	disease causing (fs/PTC)

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: rs1474473957; hg19: chr4-88928925;