NM_001009944.3:c.7708T>C

Variant names:

• chr16-2106020-A-G
• rs28575767
• NM_001009944.3:c.7708T>C

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001009944.3(PKD1):​c.7708T>C​(p.Leu2570Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0945 in 1,549,208 control chromosomes in the GnomAD database, including 13,182 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.20 (4977 hom., cov: 31)
  • Exomes 𝑓: 0.084 (8205 hom.)
• Consequence: PKD1 NM_001009944.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 0.601
• Publications: 7 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=-0.7).
• BP6: Variant 16-2106020-A-G is Benign according to our data. Variant chr16-2106020-A-G is described in ClinVar as Benign. ClinVar VariationId is 257004.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.601 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.45 is higher than 0.05.

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.7708T>C	p.Leu2570Leu	synonymous	Exon 20 of 46	NP_001009944.3	P98161-1
	PKD1	NM_000296.4		c.7708T>C	p.Leu2570Leu	synonymous	Exon 20 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.7708T>C	p.Leu2570Leu	synonymous	Exon 20 of 46	ENSP00000262304.4	P98161-1
	PKD1	ENST00000423118.5	TSL:1	c.7708T>C	p.Leu2570Leu	synonymous	Exon 20 of 46	ENSP00000399501.1	P98161-3
	PKD1	ENST00000415938.7	TSL:5	n.953T>C		non_coding_transcript_exon	Exon 6 of 17

Frequencies

GnomAD3 genomes AF: 0.195 AC: 29564 AN: 151464 Hom.: 4953 Cov.: 31

Gnomad AFR AF: 0.455

Gnomad AMI AF: 0.121

Gnomad AMR AF: 0.134

Gnomad ASJ AF: 0.159

Gnomad EAS AF: 0.000588

Gnomad SAS AF: 0.0281

Gnomad FIN AF: 0.0763

Gnomad MID AF: 0.188

Gnomad NFE AF: 0.0994

Gnomad OTH AF: 0.190

GnomAD2 exomes AF: 0.0915 AC: 21468 AN: 234616 AF XY: 0.0856

Gnomad AFR exome AF: 0.451

Gnomad AMR exome AF: 0.0758

Gnomad ASJ exome AF: 0.139

Gnomad EAS exome AF: 0.0000556

Gnomad FIN exome AF: 0.0555

Gnomad NFE exome AF: 0.0876

Gnomad OTH exome AF: 0.106

GnomAD4 exome AF: 0.0836 AC: 116839 AN: 1397626 Hom.: 8205 Cov.: 34 AF XY: 0.0817 AC XY: 56971 AN XY: 696988

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

African (AFR) AF: 0.455 AC: 13842 AN: 30452

American (AMR) AF: 0.0872 AC: 3872 AN: 44390

Ashkenazi Jewish (ASJ) AF: 0.143 AC: 3649 AN: 25598

East Asian (EAS) AF: 0.000176 AC: 7 AN: 39692

South Asian (SAS) AF: 0.0302 AC: 2587 AN: 85788

European-Finnish (FIN) AF: 0.0647 AC: 3137 AN: 48470

Middle Eastern (MID) AF: 0.155 AC: 612 AN: 3950

European-Non Finnish (NFE) AF: 0.0782 AC: 82991 AN: 1061044

Other (OTH) AF: 0.105 AC: 6142 AN: 58242

⚠️ 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 AF: 0.195 AC: 29634 AN: 151582 Hom.: 4977 Cov.: 31 AF XY: 0.188 AC XY: 13937 AN XY: 74076

African (AFR) AF: 0.456 AC: 18789 AN: 41238

American (AMR) AF: 0.134 AC: 2043 AN: 15226

Ashkenazi Jewish (ASJ) AF: 0.159 AC: 550 AN: 3470

East Asian (EAS) AF: 0.000589 AC: 3 AN: 5094

South Asian (SAS) AF: 0.0277 AC: 133 AN: 4804

European-Finnish (FIN) AF: 0.0763 AC: 804 AN: 10534

Middle Eastern (MID) AF: 0.195 AC: 57 AN: 292

European-Non Finnish (NFE) AF: 0.0994 AC: 6750 AN: 67914

Other (OTH) AF: 0.188 AC: 395 AN: 2104

Alfa AF: 0.0755 Hom.: 135

Bravo AF: 0.215

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	2	not specified (2)
-	-	1	Autosomal dominant polycystic kidney disease (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	-0.70
CADD	Benign	2.2
DANN	Benign	0.54
PhyloP100		0.60
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs28575767; hg19: chr16-2156021; COSMIC: COSV51917030; COSMIC: COSV51917030;