rs1057518906

Variant names:

• chr4-88007878-C-T
• rs1057518906
• NM_000297.4:c.145C>T
• PKD2 p.Gln49*

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_000297.4(PKD2):​c.145C>T​(p.Gln49*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000305 in 1,311,678 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000017 (0 hom.)
• Consequence: PKD2 NM_000297.4 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 1.76
• Publications: 1 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: Genomics England PanelApp, Ambry Genetics, Labcorp Genetics (formerly Invitae)

ENSG00000286618 (HGNC:):

ACMG classification

Our verdict: Pathogenic. The variant received 18 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 4-88007878-C-T is Pathogenic according to our data. Variant chr4-88007878-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 374110.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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.145C>T	p.Gln49*	stop_gained	Exon 1 of 15	NP_000288.1	Q13563-1
	PKD2	NM_001440544.1		c.145C>T	p.Gln49*	stop_gained	Exon 1 of 14	NP_001427473.1
	PKD2	NR_156488.2		n.244C>T		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.145C>T	p.Gln49*	stop_gained	Exon 1 of 15	ENSP00000237596.2	Q13563-1
	PKD2	ENST00000927447.1		c.145C>T	p.Gln49*	stop_gained	Exon 1 of 15	ENSP00000597506.1
	PKD2	ENST00000927448.1		c.145C>T	p.Gln49*	stop_gained	Exon 1 of 14	ENSP00000597507.1

Frequencies

GnomAD3 genomes AF: 0.0000133 AC: 2 AN: 150548 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.0000296

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000172 AC: 2 AN: 1161130 Hom.: 0 Cov.: 33 AF XY: 0.00000178 AC XY: 1 AN XY: 560354

African (AFR) AF: 0.00 AC: 0 AN: 24620

American (AMR) AF: 0.00 AC: 0 AN: 17632

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 17298

East Asian (EAS) AF: 0.00 AC: 0 AN: 26300

South Asian (SAS) AF: 0.00 AC: 0 AN: 41698

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 25288

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3322

European-Non Finnish (NFE) AF: 0.00000209 AC: 2 AN: 958400

Other (OTH) AF: 0.00 AC: 0 AN: 46572

GnomAD4 genome AF: 0.0000133 AC: 2 AN: 150548 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 73488

African (AFR) AF: 0.00 AC: 0 AN: 41224

American (AMR) AF: 0.00 AC: 0 AN: 15112

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3464

East Asian (EAS) AF: 0.00 AC: 0 AN: 5098

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 9956

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 312

European-Non Finnish (NFE) AF: 0.0000296 AC: 2 AN: 67566

Other (OTH) AF: 0.00 AC: 0 AN: 2078

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.58
CADD	Pathogenic	36
DANN	Uncertain	1.0
Eigen	Uncertain	0.48
Eigen_PC	Benign	0.19
FATHMM_MKL	Benign	0.39	N
PhyloP100		1.8
PromoterAI		-0.031	Neutral
Mutation Taster		=2/198	disease causing (ClinVar)

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs1057518906;

hg19: chr4-88929030;