rs139752541

Variant names:

• chr16-2104622-T-C
• rs139752541
• NM_001009944.3:c.8037A>G

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_001009944.3(PKD1):​c.8037A>G​(p.Val2679Val) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00171 in 1,575,952 control chromosomes in the GnomAD database, including 42 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0084 (20 hom., cov: 20)
  • Exomes 𝑓: 0.0010 (22 hom.)
• Consequence: PKD1 NM_001009944.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 0.160
• Publications: 0 publications found

Genes affected

PKD1 (HGNC:9008): (polycystin 1, transient receptor potential channel interacting) This gene encodes a member of the polycystin protein family. The encoded glycoprotein contains a large N-terminal extracellular region, multiple transmembrane domains and a cytoplasmic C-tail. It is an integral membrane protein that functions as a regulator of calcium permeable cation channels and intracellular calcium homoeostasis. It is also involved in cell-cell/matrix interactions and may modulate G-protein-coupled signal-transduction pathways. It plays a role in renal tubular development, and mutations in this gene cause autosomal dominant polycystic kidney disease type 1 (ADPKD1). ADPKD1 is characterized by the growth of fluid-filled cysts that replace normal renal tissue and result in end-stage renal failure. Splice variants encoding different isoforms have been noted for this gene. Also, six pseudogenes, closely linked in a known duplicated region on chromosome 16p, have been described. [provided by RefSeq, Oct 2008]

PKD1 Gene-Disease associations (from GenCC):

• autosomal dominant polycystic kidney disease

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, ClinGen
• polycystic kidney disease 1

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Laboratory for Molecular Medicine, Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
• autosomal recessive polycystic kidney disease

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• Caroli disease

  Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.5).
• BP6: Variant 16-2104622-T-C is Benign according to our data. Variant chr16-2104622-T-C is described in ClinVar as Benign. ClinVar VariationId is 440141.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.16 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0084 (1236/147126) while in subpopulation AFR AF = 0.0295 (1161/39352). AF 95% confidence interval is 0.0281. There are 20 homozygotes in GnomAd4. There are 597 alleles in the male GnomAd4 subpopulation. Median coverage is 20. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 20 AD,AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001009944.3. 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
	PKD1	NM_001009944.3	MANE Select	c.8037A>G	p.Val2679Val	synonymous	Exon 22 of 46	NP_001009944.3	P98161-1
	PKD1	NM_000296.4		c.8037A>G	p.Val2679Val	synonymous	Exon 22 of 46	NP_000287.4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PKD1	ENST00000262304.9	TSL:1 MANE Select	c.8037A>G	p.Val2679Val	synonymous	Exon 22 of 46	ENSP00000262304.4	P98161-1
	PKD1	ENST00000423118.5	TSL:1	c.8037A>G	p.Val2679Val	synonymous	Exon 22 of 46	ENSP00000399501.1	P98161-3
	PKD1	ENST00000567946.1	TSL:5	c.96A>G	p.Val32Val	synonymous	Exon 2 of 12	ENSP00000457984.1	H3BV77

Frequencies

GnomAD3 genomes AF: 0.00838 AC: 1232 AN: 147006 Hom.: 19 Cov.: 20

Gnomad AFR AF: 0.0295

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00359

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000220

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00654

Gnomad NFE AF: 0.000120

Gnomad OTH AF: 0.00548

GnomAD2 exomes AF: 0.00217 AC: 310 AN: 143122 AF XY: 0.00176

Gnomad AFR exome AF: 0.0345

Gnomad AMR exome AF: 0.00156

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000134

Gnomad NFE exome AF: 0.000196

Gnomad OTH exome AF: 0.000702

GnomAD4 exome AF: 0.00102 AC: 1453 AN: 1428826 Hom.: 22 Cov.: 28 AF XY: 0.000868 AC XY: 618 AN XY: 711612

African (AFR) AF: 0.0329 AC: 1079 AN: 32762

American (AMR) AF: 0.00178 AC: 78 AN: 43882

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25770

East Asian (EAS) AF: 0.00 AC: 0 AN: 39322

South Asian (SAS) AF: 0.0000711 AC: 6 AN: 84444

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 47234

Middle Eastern (MID) AF: 0.000976 AC: 4 AN: 4098

European-Non Finnish (NFE) AF: 0.000149 AC: 163 AN: 1092116

Other (OTH) AF: 0.00208 AC: 123 AN: 59198

GnomAD4 genome AF: 0.00840 AC: 1236 AN: 147126 Hom.: 20 Cov.: 20 AF XY: 0.00835 AC XY: 597 AN XY: 71538

African (AFR) AF: 0.0295 AC: 1161 AN: 39352

American (AMR) AF: 0.00358 AC: 53 AN: 14802

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3430

East Asian (EAS) AF: 0.00 AC: 0 AN: 4674

South Asian (SAS) AF: 0.000220 AC: 1 AN: 4540

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10312

Middle Eastern (MID) AF: 0.00704 AC: 2 AN: 284

European-Non Finnish (NFE) AF: 0.000120 AC: 8 AN: 66800

Other (OTH) AF: 0.00542 AC: 11 AN: 2030

Alfa AF: 0.00391 Hom.: 1

Bravo AF: 0.00997

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (4)
-	-	2	not provided (2)
-	-	1	PKD1-related disorder (1)
-	-	1	Polycystic kidney disease (1)
-	-	1	Polycystic kidney disease, adult type (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.50
CADD	Benign	7.7
DANN	Benign	0.75
PhyloP100		0.16
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		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: rs139752541; hg19: chr16-2154623;