16-2103870-C-T

Variant names:

• chr16-2103870-C-T
• rs28674911
• NM_001009944.3:c.8187G>A

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.8187G>A​(p.Ser2729Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0011 in 1,588,834 control chromosomes in the GnomAD database, including 22 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0051 (16 hom., cov: 28)
  • Exomes 𝑓: 0.00071 (6 hom.)
• Consequence: PKD1 NM_001009944.3 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -5.68
• Publications: 1 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=-0.75).
• BP6: Variant 16-2103870-C-T is Benign according to our data. Variant chr16-2103870-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 257015.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-5.68 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00514 (730/142118) while in subpopulation AFR AF = 0.0177 (667/37728). AF 95% confidence interval is 0.0166. There are 16 homozygotes in GnomAd4. There are 332 alleles in the male GnomAd4 subpopulation. Median coverage is 28. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 16 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.8187G>A	p.Ser2729Ser	synonymous	Exon 23 of 46	NP_001009944.3	P98161-1
	PKD1	NM_000296.4		c.8187G>A	p.Ser2729Ser	synonymous	Exon 23 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.8187G>A	p.Ser2729Ser	synonymous	Exon 23 of 46	ENSP00000262304.4	P98161-1
	PKD1	ENST00000423118.5	TSL:1	c.8187G>A	p.Ser2729Ser	synonymous	Exon 23 of 46	ENSP00000399501.1	P98161-3
	PKD1	ENST00000567946.1	TSL:5	c.246G>A	p.Ser82Ser	synonymous	Exon 3 of 12	ENSP00000457984.1	H3BV77

Frequencies

GnomAD3 genomes AF: 0.00511 AC: 725 AN: 141994 Hom.: 16 Cov.: 28

Gnomad AFR AF: 0.0176

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00190

Gnomad ASJ AF: 0.00147

Gnomad EAS AF: 0.00156

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00662

Gnomad NFE AF: 0.000168

Gnomad OTH AF: 0.00567

GnomAD2 exomes AF: 0.00174 AC: 415 AN: 239026 AF XY: 0.00138

Gnomad AFR exome AF: 0.0203

Gnomad AMR exome AF: 0.00113

Gnomad ASJ exome AF: 0.00234

Gnomad EAS exome AF: 0.00199

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000131

Gnomad OTH exome AF: 0.000851

GnomAD4 exome AF: 0.000705 AC: 1020 AN: 1446716 Hom.: 6 Cov.: 34 AF XY: 0.000599 AC XY: 431 AN XY: 719428

African (AFR) AF: 0.0205 AC: 678 AN: 33030

American (AMR) AF: 0.00118 AC: 52 AN: 43906

Ashkenazi Jewish (ASJ) AF: 0.00148 AC: 38 AN: 25750

East Asian (EAS) AF: 0.000897 AC: 35 AN: 39000

South Asian (SAS) AF: 0.000163 AC: 14 AN: 85708

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50860

Middle Eastern (MID) AF: 0.00197 AC: 8 AN: 4066

European-Non Finnish (NFE) AF: 0.000101 AC: 112 AN: 1104976

Other (OTH) AF: 0.00140 AC: 83 AN: 59420

GnomAD4 genome AF: 0.00514 AC: 730 AN: 142118 Hom.: 16 Cov.: 28 AF XY: 0.00483 AC XY: 332 AN XY: 68788

African (AFR) AF: 0.0177 AC: 667 AN: 37728

American (AMR) AF: 0.00190 AC: 27 AN: 14216

Ashkenazi Jewish (ASJ) AF: 0.00147 AC: 5 AN: 3402

East Asian (EAS) AF: 0.00157 AC: 7 AN: 4468

South Asian (SAS) AF: 0.00 AC: 0 AN: 4086

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 9538

Middle Eastern (MID) AF: 0.00709 AC: 2 AN: 282

European-Non Finnish (NFE) AF: 0.000168 AC: 11 AN: 65582

Other (OTH) AF: 0.00561 AC: 11 AN: 1962

Alfa AF: 0.00294 Hom.: 4

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not specified (3)
-	-	1	Autosomal dominant polycystic kidney disease (1)
-	-	1	not provided (1)
-	-	1	Polycystic kidney disease (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.75
CADD	Benign	0.86
DANN	Benign	0.53
PhyloP100		-5.7
RBP_binding_hub_radar		0.92
RBP_regulation_power_radar		2.0
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs28674911; hg19: chr16-2153871; COSMIC: COSV51922822; COSMIC: COSV51922822;