4-88007720-C-A

Position:

• chr4-88007720-C-A

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_000297.4(PKD2):​c.-14C>A variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000126 in 1,193,158 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (no stars).

• Frequency:
  • Genomes: 𝑓 0.00067 (1 hom., cov: 32)
  • Exomes 𝑓: 0.000047 (0 hom.)
• Consequence: PKD2 NM_000297.4 5_prime_UTR
• Clinical Significance: Likely benign no assertion criteria provided B:1
• Conservation: PhyloP100: 0.282

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]

(HGNC:):

ACMG classification

Verdict is Benign. Variant got -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.67).
• BP6: Variant 4-88007720-C-A is Benign according to our data. Variant chr4-88007720-C-A is described in ClinVar as [Likely_benign]. Clinvar id is 997305.Status of the report is no_assertion_criteria_provided, 0 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.000674 (101/149952) while in subpopulation AFR AF= 0.00232 (96/41292). AF 95% confidence interval is 0.00195. There are 1 homozygotes in gnomad4. There are 50 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 101 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PKD2	NM_000297.4	c.-14C>A		5_prime_UTR_variant	1/15	ENST00000237596.7
PKD2	XM_011532028.3	c.-14C>A		5_prime_UTR_variant	1/14
PKD2	NR_156488.2	n.86C>A		non_coding_transcript_exon_variant	1/14

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PKD2	ENST00000237596.7	c.-14C>A		5_prime_UTR_variant	1/15	1	NM_000297.4	P1
	ENST00000662475.1	n.112+646G>T		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.000674 AC: 101 AN: 149844 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.00233

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000199

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: 0.00

Gnomad OTH AF: 0.000966

GnomAD3 exomes AF: 0.0000207 AC: 1 AN: 48406 Hom.: 0 AF XY: 0.0000338 AC XY: 1 AN XY: 29612

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000146

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS 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: 0.0000470 AC: 49 AN: 1043206 Hom.: 0 Cov.: 28 AF XY: 0.0000474 AC XY: 24 AN XY: 506540

Gnomad4 AFR exome AF: 0.00199

Gnomad4 AMR exome AF: 0.0000813

Gnomad4 ASJ exome AF: 0.0000741

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.000183

GnomAD4 genome AF: 0.000674 AC: 101 AN: 149952 Hom.: 1 Cov.: 32 AF XY: 0.000683 AC XY: 50 AN XY: 73244

Gnomad4 AFR AF: 0.00232

Gnomad4 AMR AF: 0.000199

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.000956

Alfa AF: 0.000214 Hom.: 0

Bravo AF: 0.000786

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

Submissions by phenotype

Polycystic kidney disease Benign:1

Likely benign, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

-

The PKD2 c.-14C>A variant was not identified in the literature nor was it identified in the ClinVar, LOVD 3.0, ADPKD Mutation Database, PKD1-LOVD, databases. The variant was identified in dbSNP (ID: rs552115097) as “NA”. The variant was identified in control databases in 21 (1 homozygous) of 28212 chromosomes at a frequency of 0.0007 in the following population: African in 21 of 8368 chromosomes (freq. 0.0025) increasing the likelihood that this may be a low frequency variant in certain populations of origin (Genome Aggregation Consortium Feb 27, 2017). The c.-14C>A variant occurs outside of the splicing consensus sequence and 1 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict a greater than 10% difference in splicing; this is not very predictive of pathogenicity. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.67
CADD	Benign	13
DANN	Benign	0.81

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

Publications

LitVar

Other links and lift over

dbSNP: rs552115097; hg19: chr4-88928872;