rs141557400

Variant names:

• chr16-2110322-G-A
• rs141557400
• NM_001009944.3:c.4845C>T

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.4845C>T​(p.Asn1615Asn) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00509 in 1,612,636 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 0.0035 (0 hom., cov: 34)
  • Exomes 𝑓: 0.0053 (22 hom.)
• Consequence: PKD1 NM_001009944.3 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: -0.162
• 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: ClinGen, Orphanet
• 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=-0.59).
• BP6: Variant 16-2110322-G-A is Benign according to our data. Variant chr16-2110322-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 256970.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.162 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00346 (527/152336) while in subpopulation NFE AF = 0.00559 (380/68028). AF 95% confidence interval is 0.00512. There are 0 homozygotes in GnomAd4. There are 240 alleles in the male GnomAd4 subpopulation. Median coverage is 34. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 22 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PKD1	NM_001009944.3	MANE Select	c.4845C>T	p.Asn1615Asn	synonymous	Exon 15 of 46	NP_001009944.3
	PKD1	NM_000296.4		c.4845C>T	p.Asn1615Asn	synonymous	Exon 15 of 46	NP_000287.4

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PKD1	ENST00000262304.9	TSL:1 MANE Select	c.4845C>T	p.Asn1615Asn	synonymous	Exon 15 of 46	ENSP00000262304.4
	PKD1	ENST00000423118.5	TSL:1	c.4845C>T	p.Asn1615Asn	synonymous	Exon 15 of 46	ENSP00000399501.1
	PKD1	ENST00000488185.2	TSL:5	c.471-1964C>T		intron	N/A	ENSP00000456672.1

Frequencies

GnomAD3 genomes AF: 0.00346 AC: 527 AN: 152218 Hom.: 0 Cov.: 34

Gnomad AFR AF: 0.000965

Gnomad AMI AF: 0.00987

Gnomad AMR AF: 0.00478

Gnomad ASJ AF: 0.00432

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00145

Gnomad FIN AF: 0.000188

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00559

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.00310 AC: 773 AN: 249432 AF XY: 0.00309

Gnomad AFR exome AF: 0.000746

Gnomad AMR exome AF: 0.00220

Gnomad ASJ exome AF: 0.00441

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000508

Gnomad NFE exome AF: 0.00515

Gnomad OTH exome AF: 0.00312

GnomAD4 exome AF: 0.00527 AC: 7689 AN: 1460300 Hom.: 22 Cov.: 36 AF XY: 0.00519 AC XY: 3767 AN XY: 726440

African (AFR) AF: 0.000807 AC: 27 AN: 33472

American (AMR) AF: 0.00219 AC: 98 AN: 44712

Ashkenazi Jewish (ASJ) AF: 0.00425 AC: 111 AN: 26132

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39700

South Asian (SAS) AF: 0.000962 AC: 83 AN: 86250

European-Finnish (FIN) AF: 0.000538 AC: 28 AN: 52092

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5760

European-Non Finnish (NFE) AF: 0.00640 AC: 7117 AN: 1111820

Other (OTH) AF: 0.00369 AC: 223 AN: 60362

GnomAD4 genome AF: 0.00346 AC: 527 AN: 152336 Hom.: 0 Cov.: 34 AF XY: 0.00322 AC XY: 240 AN XY: 74488

African (AFR) AF: 0.000962 AC: 40 AN: 41572

American (AMR) AF: 0.00477 AC: 73 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.00432 AC: 15 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.00145 AC: 7 AN: 4832

European-Finnish (FIN) AF: 0.000188 AC: 2 AN: 10624

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00559 AC: 380 AN: 68028

Other (OTH) AF: 0.000473 AC: 1 AN: 2116

Alfa AF: 0.00468 Hom.: 0

Bravo AF: 0.00372

EpiCase AF: 0.00431

EpiControl AF: 0.00569

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not provided (5)
-	-	3	not specified (3)
-	-	2	Polycystic kidney disease, adult type (2)
-	-	1	Polycystic kidney disease (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.59
CADD	Benign	0.47
DANN	Benign	0.76
PhyloP100		-0.16
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
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: rs141557400; hg19: chr16-2160323; COSMIC: COSV51918097; COSMIC: COSV51918097;