NM_000297.4:c.19G>A

Variant names:

• chr4-88007752-G-A
• rs1366782791
• NM_000297.4:c.19G>A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_000297.4(PKD2):​c.19G>A​(p.Val7Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000474 in 1,054,000 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000047 (0 hom.)
• Consequence: PKD2 NM_000297.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 1.63
• 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

ENSG00000286618 (HGNC:):

ENSG00000289034 (HGNC:58844):

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.18531457).

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.19G>A	p.Val7Met	missense	Exon 1 of 15	NP_000288.1	Q13563-1
	PKD2	NM_001440544.1		c.19G>A	p.Val7Met	missense	Exon 1 of 14	NP_001427473.1
	PKD2	NR_156488.2		n.118G>A		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.19G>A	p.Val7Met	missense	Exon 1 of 15	ENSP00000237596.2	Q13563-1
	PKD2	ENST00000927447.1		c.19G>A	p.Val7Met	missense	Exon 1 of 15	ENSP00000597506.1
	PKD2	ENST00000927448.1		c.19G>A	p.Val7Met	missense	Exon 1 of 14	ENSP00000597507.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.0000531 AC: 3 AN: 56528 AF XY: 0.0000592

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.000191

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000474 AC: 5 AN: 1054000 Hom.: 0 Cov.: 28 AF XY: 0.00000390 AC XY: 2 AN XY: 512476

African (AFR) AF: 0.00 AC: 0 AN: 20548

American (AMR) AF: 0.00 AC: 0 AN: 15212

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 14250

East Asian (EAS) AF: 0.00 AC: 0 AN: 14430

South Asian (SAS) AF: 0.000123 AC: 5 AN: 40750

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 16354

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2844

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 890866

Other (OTH) AF: 0.00 AC: 0 AN: 38746

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	-	Autosomal dominant polycystic kidney disease (1)
-	1	-	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.32
BayesDel_addAF	Benign	-0.043	T
BayesDel_noAF	Benign	-0.30
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.21	T
Eigen	Benign	-0.35
Eigen_PC	Benign	-0.36
FATHMM_MKL	Benign	0.16	N
LIST_S2	Benign	0.64	T
M_CAP	Pathogenic	0.54	D
MetaRNN	Benign	0.19	T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	0.81	L
PhyloP100		1.6
PrimateAI	Pathogenic	0.93	D
PROVEAN	Benign	-0.44	N
REVEL	Benign	0.10
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		0.68	P
Vest4		0.17
MutPred		0.22		Gain of glycosylation at S4 (P = 0.0079)
MVP		0.32
MPC		0.63
ClinPred		0.27	T
GERP RS		1.8
PromoterAI		0.040	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.26
gMVP		0.49
Mutation Taster		=84/16	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: rs1366782791; hg19: chr4-88928904;