chr4-88008021-CGAG-C

Variant names:

• chr4-88008021-CGAG-C
• rs750077647
• NM_000297.4:c.305_307delAGG

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 0P and 3B. BP3 BP6_Moderate

The NM_000297.4(PKD2):​c.305_307delAGG​(p.Glu102del) variant causes a disruptive inframe deletion change. The variant allele was found at a frequency of 0.00728 in 1,219,582 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.00020 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0073 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: PKD2 NM_000297.4 disruptive_inframe_deletion
• Clinical Significance: Benign criteria provided, single submitter B:3
• 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: Likely_benign. The variant received -3 ACMG points.

• BP3: Nonframeshift variant in repetitive region in NM_000297.4
• BP6: Variant 4-88008021-CGAG-C is Benign according to our data. Variant chr4-88008021-CGAG-C is described in ClinVar as Benign. ClinVar VariationId is 219942.Status of the report is criteria_provided_single_submitter, 1 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PKD2	NM_000297.4	MANE Select	c.305_307delAGG	p.Glu102del	disruptive_inframe_deletion	Exon 1 of 15	NP_000288.1
	PKD2	NM_001440544.1		c.305_307delAGG	p.Glu102del	disruptive_inframe_deletion	Exon 1 of 14	NP_001427473.1
	PKD2	NR_156488.2		n.404_406delAGG		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.305_307delAGG	p.Glu102del	disruptive_inframe_deletion	Exon 1 of 15	ENSP00000237596.2
	ENSG00000286618	ENST00000662475.1		n.112+342_112+344delCTC		intron	N/A
	PKD2	ENST00000506727.1	TSL:4	n.-210_-208delGAG		upstream_gene	N/A

Frequencies

GnomAD3 genomes AF: 0.000200 AC: 30 AN: 150308 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000242

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000331

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000606

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000252

Gnomad OTH AF: 0.000484

GnomAD2 exomes AF: 0.0244 AC: 2381 AN: 97700 AF XY: 0.0232

Gnomad AFR exome AF: 0.0575

Gnomad AMR exome AF: 0.0171

Gnomad ASJ exome AF: 0.00999

Gnomad EAS exome AF: 0.0583

Gnomad FIN exome AF: 0.00609

Gnomad NFE exome AF: 0.0277

Gnomad OTH exome AF: 0.0330

GnomAD4 exome AF: 0.00728 AC: 8882 AN: 1219582 Hom.: 0 AF XY: 0.00751 AC XY: 4460 AN XY: 594154

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

African (AFR) AF: 0.0102 AC: 281 AN: 27494

American (AMR) AF: 0.0149 AC: 431 AN: 28986

Ashkenazi Jewish (ASJ) AF: 0.0102 AC: 217 AN: 21238

East Asian (EAS) AF: 0.0156 AC: 467 AN: 29868

South Asian (SAS) AF: 0.0157 AC: 928 AN: 59114

European-Finnish (FIN) AF: 0.00959 AC: 264 AN: 27528

Middle Eastern (MID) AF: 0.00568 AC: 29 AN: 5106

European-Non Finnish (NFE) AF: 0.00600 AC: 5820 AN: 970022

Other (OTH) AF: 0.00886 AC: 445 AN: 50226

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.000199 AC: 30 AN: 150398 Hom.: 0 Cov.: 32 AF XY: 0.000218 AC XY: 16 AN XY: 73428

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

African (AFR) AF: 0.0000242 AC: 1 AN: 41362

American (AMR) AF: 0.000331 AC: 5 AN: 15124

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3442

East Asian (EAS) AF: 0.00 AC: 0 AN: 5132

South Asian (SAS) AF: 0.00 AC: 0 AN: 4818

European-Finnish (FIN) AF: 0.000606 AC: 6 AN: 9898

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.000252 AC: 17 AN: 67334

Other (OTH) AF: 0.000480 AC: 1 AN: 2084

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.00000000563408), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.0325 Hom.: 1

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:2

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Autosomal dominant polycystic kidney disease Benign:1

Nov 30, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		4.0
Mutation Taster		=67/33	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: rs750077647; hg19: chr4-88929173; COSMIC: COSV52938297; COSMIC: COSV52938297;