rs143265128

Variant names:

• chr16-2103810-C-T
• rs143265128
• NM_001009944.3:c.8247G>A

Your query was ambiguous. Multiple possible variants found:

• chr16-2103810-C-T
• chr16-2103810-C-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.8247G>A​(p.Ala2749Ala) 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 1,608,824 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0010 (0 hom., cov: 30)
  • Exomes 𝑓: 0.0011 (2 hom.)
• Consequence: PKD1 NM_001009944.3 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -1.46
• 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=-0.57).
• BP6: Variant 16-2103810-C-T is Benign according to our data. Variant chr16-2103810-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 440127.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.46 with no splicing effect.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.00101 (152/150810) while in subpopulation AMR AF = 0.0023 (35/15198). AF 95% confidence interval is 0.0017. There are 0 homozygotes in GnomAd4. There are 64 alleles in the male GnomAd4 subpopulation. Median coverage is 30. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 2 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.8247G>A	p.Ala2749Ala	synonymous	Exon 23 of 46	NP_001009944.3	P98161-1
	PKD1	NM_000296.4		c.8247G>A	p.Ala2749Ala	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.8247G>A	p.Ala2749Ala	synonymous	Exon 23 of 46	ENSP00000262304.4	P98161-1
	PKD1	ENST00000423118.5	TSL:1	c.8247G>A	p.Ala2749Ala	synonymous	Exon 23 of 46	ENSP00000399501.1	P98161-3
	PKD1	ENST00000567946.1	TSL:5	c.306G>A	p.Ala102Ala	synonymous	Exon 3 of 12	ENSP00000457984.1	H3BV77

Frequencies

GnomAD3 genomes AF: 0.00101 AC: 152 AN: 150692 Hom.: 0 Cov.: 30

Gnomad AFR AF: 0.000710

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00231

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000953

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00127

Gnomad OTH AF: 0.000482

GnomAD2 exomes AF: 0.000790 AC: 195 AN: 246752 AF XY: 0.000765

Gnomad AFR exome AF: 0.000325

Gnomad AMR exome AF: 0.00189

Gnomad ASJ exome AF: 0.000101

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000465

Gnomad NFE exome AF: 0.00101

Gnomad OTH exome AF: 0.00116

GnomAD4 exome AF: 0.00110 AC: 1610 AN: 1458014 Hom.: 2 Cov.: 34 AF XY: 0.00101 AC XY: 729 AN XY: 725308

African (AFR) AF: 0.000359 AC: 12 AN: 33392

American (AMR) AF: 0.00177 AC: 79 AN: 44698

Ashkenazi Jewish (ASJ) AF: 0.0000766 AC: 2 AN: 26124

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39698

South Asian (SAS) AF: 0.0000697 AC: 6 AN: 86142

European-Finnish (FIN) AF: 0.0000576 AC: 3 AN: 52052

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4138

European-Non Finnish (NFE) AF: 0.00129 AC: 1432 AN: 1111602

Other (OTH) AF: 0.00123 AC: 74 AN: 60168

GnomAD4 genome AF: 0.00101 AC: 152 AN: 150810 Hom.: 0 Cov.: 30 AF XY: 0.000870 AC XY: 64 AN XY: 73574

African (AFR) AF: 0.000707 AC: 29 AN: 40994

American (AMR) AF: 0.00230 AC: 35 AN: 15198

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3464

East Asian (EAS) AF: 0.00 AC: 0 AN: 4968

South Asian (SAS) AF: 0.00 AC: 0 AN: 4724

European-Finnish (FIN) AF: 0.0000953 AC: 1 AN: 10488

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 290

European-Non Finnish (NFE) AF: 0.00127 AC: 86 AN: 67680

Other (OTH) AF: 0.000477 AC: 1 AN: 2096

Alfa AF: 0.000672 Hom.: 0

Bravo AF: 0.00107

EpiCase AF: 0.00125

EpiControl AF: 0.00107

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.57
CADD	Benign	2.8
DANN	Benign	0.91
PhyloP100		-1.5
Mutation Taster		=100/0	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: rs143265128; hg19: chr16-2153811; COSMIC: COSV51919145; COSMIC: COSV51919145;