16-2108622-T-C

Variant names:

• chr16-2108622-T-C
• rs147685291
• NM_001009944.3:c.6545A>G

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 2P and 20B. PM5 BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001009944.3(PKD1):​c.6545A>G​(p.Gln2182Arg) variant causes a missense change. The variant allele was found at a frequency of 0.000877 in 1,560,074 control chromosomes in the GnomAD database, including 19 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense has been classified as Likely pathogenic.

• Frequency:
  • Genomes: 𝑓 0.0045 (13 hom., cov: 33)
  • Exomes 𝑓: 0.00048 (6 hom.)
• Consequence: PKD1 NM_001009944.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 3.72
• Publications: 4 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 -18 ACMG points.

• PM5: Other missense variant is known to change same aminoacid residue: Variant chr16-2108564-TGGGCGCCCCGGCCGCTGGCAGCTGGCGGTGCGATACACCTCCCAGCGGTACTCAGTCT-CGAGC is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 2136066.
• BP4: Computational evidence support a benign effect (MetaRNN=0.010542333).
• BP6: Variant 16-2108622-T-C is Benign according to our data. Variant chr16-2108622-T-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 433974.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00455 (693/152320) while in subpopulation AFR AF = 0.016 (666/41574). AF 95% confidence interval is 0.015. There are 13 homozygotes in GnomAd4. There are 318 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 13 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.6545A>G	p.Gln2182Arg	missense	Exon 15 of 46	NP_001009944.3	P98161-1
	PKD1	NM_000296.4		c.6545A>G	p.Gln2182Arg	missense	Exon 15 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.6545A>G	p.Gln2182Arg	missense	Exon 15 of 46	ENSP00000262304.4	P98161-1
	PKD1	ENST00000423118.5	TSL:1	c.6545A>G	p.Gln2182Arg	missense	Exon 15 of 46	ENSP00000399501.1	P98161-3
	PKD1	ENST00000488185.2	TSL:5	c.471-264A>G		intron	N/A	ENSP00000456672.1	H3BSE9

Frequencies

GnomAD3 genomes AF: 0.00455 AC: 693 AN: 152202 Hom.: 13 Cov.: 33

Gnomad AFR AF: 0.0161

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000916

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00478

GnomAD2 exomes AF: 0.00120 AC: 205 AN: 170732 AF XY: 0.000822

Gnomad AFR exome AF: 0.0183

Gnomad AMR exome AF: 0.000731

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000214

GnomAD4 exome AF: 0.000479 AC: 675 AN: 1407754 Hom.: 6 Cov.: 34 AF XY: 0.000398 AC XY: 277 AN XY: 695372

African (AFR) AF: 0.0183 AC: 595 AN: 32454

American (AMR) AF: 0.000783 AC: 29 AN: 37028

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25248

East Asian (EAS) AF: 0.00 AC: 0 AN: 36902

South Asian (SAS) AF: 0.0000124 AC: 1 AN: 80478

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 48338

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4112

European-Non Finnish (NFE) AF: 0.00000184 AC: 2 AN: 1084942

Other (OTH) AF: 0.000824 AC: 48 AN: 58252

GnomAD4 genome AF: 0.00455 AC: 693 AN: 152320 Hom.: 13 Cov.: 33 AF XY: 0.00427 AC XY: 318 AN XY: 74484

African (AFR) AF: 0.0160 AC: 666 AN: 41574

American (AMR) AF: 0.000915 AC: 14 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

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

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

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

European-Non Finnish (NFE) AF: 0.0000441 AC: 3 AN: 68014

Other (OTH) AF: 0.00473 AC: 10 AN: 2116

Alfa AF: 0.00134 Hom.: 2

Bravo AF: 0.00532

ESP6500AA AF: 0.0133 AC: 57

ESP6500EA AF: 0.000118 AC: 1

ExAC AF: 0.00118 AC: 135

Asia WGS AF: 0.000578 AC: 2 AN: 3476

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.075
BayesDel_addAF	Benign	-0.41	T
BayesDel_noAF	Benign	-0.35
CADD	Benign	21
DANN	Benign	0.73
DEOGEN2	Benign	0.24	T
Eigen	Uncertain	0.26
Eigen_PC	Uncertain	0.31
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Benign	0.56	T
MetaRNN	Benign	0.011	T
MetaSVM	Benign	-0.68	T
MutationAssessor	Uncertain	2.1	M
PhyloP100		3.7
PrimateAI	Uncertain	0.59	T
PROVEAN	Benign	-0.85	N
REVEL	Benign	0.23
Sift	Benign	0.58	T
Sift4G	Uncertain	0.060	T
Polyphen		0.87	P
Vest4		0.58
MVP		0.87
ClinPred		0.051	T
GERP RS		4.4
Varity_R		0.16
gMVP		0.55
Mutation Taster		=52/48	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: rs147685291; hg19: chr16-2158623; COSMIC: COSV51919033; COSMIC: COSV51919033;