chr16-2108502-G-A

Variant names:

• chr16-2108502-G-A
• rs148496347
• NM_001009944.3:c.6665C>T

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 2P and 9B. PM1 BP4_Strong BP6 BS1

The NM_001009944.3(PKD1):​c.6665C>T​(p.Ala2222Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00135 in 1,608,720 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A2222T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00089 (1 hom., cov: 33)
  • Exomes 𝑓: 0.0014 (1 hom.)
• Consequence: PKD1 NM_001009944.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:9
• Conservation: PhyloP100: 2.63
• 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 -7 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 12 uncertain in NM_001009944.3
• BP4: Computational evidence support a benign effect (MetaRNN=0.03919947).
• BP6: Variant 16-2108502-G-A is Benign according to our data. Variant chr16-2108502-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 447995.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.000893 (136/152310) while in subpopulation NFE AF = 0.00173 (118/68012). AF 95% confidence interval is 0.00148. There are 1 homozygotes in GnomAd4. There are 65 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

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.6665C>T	p.Ala2222Val	missense	Exon 15 of 46	NP_001009944.3	P98161-1
	PKD1	NM_000296.4		c.6665C>T	p.Ala2222Val	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.6665C>T	p.Ala2222Val	missense	Exon 15 of 46	ENSP00000262304.4	P98161-1
	PKD1	ENST00000423118.5	TSL:1	c.6665C>T	p.Ala2222Val	missense	Exon 15 of 46	ENSP00000399501.1	P98161-3
	PKD1	ENST00000488185.2	TSL:5	c.471-144C>T		intron	N/A	ENSP00000456672.1	H3BSE9

Frequencies

GnomAD3 genomes AF: 0.000894 AC: 136 AN: 152196 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.000169

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.000282

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00173

Gnomad OTH AF: 0.00144

GnomAD2 exomes AF: 0.000659 AC: 157 AN: 238062 AF XY: 0.000640

Gnomad AFR exome AF: 0.0000699

Gnomad AMR exome AF: 0.000117

Gnomad ASJ exome AF: 0.000307

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000242

Gnomad NFE exome AF: 0.00133

Gnomad OTH exome AF: 0.000687

GnomAD4 exome AF: 0.00140 AC: 2042 AN: 1456410 Hom.: 1 Cov.: 34 AF XY: 0.00135 AC XY: 980 AN XY: 724540

African (AFR) AF: 0.000360 AC: 12 AN: 33378

American (AMR) AF: 0.000179 AC: 8 AN: 44674

Ashkenazi Jewish (ASJ) AF: 0.000115 AC: 3 AN: 26092

East Asian (EAS) AF: 0.00 AC: 0 AN: 39668

South Asian (SAS) AF: 0.0000232 AC: 2 AN: 86154

European-Finnish (FIN) AF: 0.000450 AC: 23 AN: 51150

Middle Eastern (MID) AF: 0.000484 AC: 2 AN: 4130

European-Non Finnish (NFE) AF: 0.00175 AC: 1947 AN: 1111228

Other (OTH) AF: 0.000751 AC: 45 AN: 59936

GnomAD4 genome AF: 0.000893 AC: 136 AN: 152310 Hom.: 1 Cov.: 33 AF XY: 0.000873 AC XY: 65 AN XY: 74480

African (AFR) AF: 0.000168 AC: 7 AN: 41572

American (AMR) AF: 0.000196 AC: 3 AN: 15300

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

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5184

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4832

European-Finnish (FIN) AF: 0.000282 AC: 3 AN: 10622

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.00173 AC: 118 AN: 68012

Other (OTH) AF: 0.00142 AC: 3 AN: 2112

Alfa AF: 0.00112 Hom.: 0

Bravo AF: 0.000744

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.00165 AC: 14

ExAC AF: 0.000481 AC: 57

EpiCase AF: 0.00142

EpiControl AF: 0.00160

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	3	not specified (4)
-	-	2	not provided (2)
-	-	2	Polycystic kidney disease, adult type (2)
-	1	-	Inborn genetic diseases (1)
-	-	1	PKD1-related disorder (1)
-	-	1	Polycystic kidney disease (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.098
BayesDel_addAF	Benign	-0.46	T
BayesDel_noAF	Benign	-0.46
CADD	Benign	16
DANN	Uncertain	0.99
DEOGEN2	Benign	0.24	T
Eigen	Benign	-0.21
Eigen_PC	Benign	-0.17
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Benign	0.71	T
M_CAP	Pathogenic	0.37	D
MetaRNN	Benign	0.039	T
MetaSVM	Benign	-0.82	T
MutationAssessor	Benign	2.0	M
PhyloP100		2.6
PrimateAI	Uncertain	0.48	T
PROVEAN	Benign	-1.5	N
REVEL	Benign	0.10
Sift	Benign	0.13	T
Sift4G	Pathogenic	0.0	D
Polyphen		0.30	B
Vest4		0.21
MVP		0.81
ClinPred		0.022	T
GERP RS		2.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.041
gMVP		0.68
Mutation Taster		=46/54	disease causing

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: rs148496347; hg19: chr16-2158503;