rs139971481

Variant names:

• chr16-2108418-G-A
• rs139971481
• NM_001009944.3:c.6749C>T

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 0P and 7B. BP4_Moderate BS1_Supporting BS2

The NM_001009944.3(PKD1):​c.6749C>T​(p.Thr2250Met) variant causes a missense change. The variant allele was found at a frequency of 0.00325 in 1,610,544 control chromosomes in the GnomAD database, including 16 homozygotes. In-silico tool predicts 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. T2250S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0022 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0034 (16 hom.)
• Consequence: PKD1 NM_001009944.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:2 B:7
• Conservation: PhyloP100: 4.05
• Publications: 12 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.

• BP4: Computational evidence support a benign effect (MetaRNN=0.18780598).
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.00217 (330/152336) while in subpopulation AMR AF = 0.00464 (71/15312). AF 95% confidence interval is 0.00377. There are 0 homozygotes in GnomAd4. There are 143 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High Homozygotes in GnomAdExome4 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.6749C>T	p.Thr2250Met	missense	Exon 15 of 46	NP_001009944.3	P98161-1
	PKD1	NM_000296.4		c.6749C>T	p.Thr2250Met	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.6749C>T	p.Thr2250Met	missense	Exon 15 of 46	ENSP00000262304.4	P98161-1
	PKD1	ENST00000423118.5	TSL:1	c.6749C>T	p.Thr2250Met	missense	Exon 15 of 46	ENSP00000399501.1	P98161-3
	PKD1	ENST00000488185.2	TSL:5	c.471-60C>T		intron	N/A	ENSP00000456672.1	H3BSE9

Frequencies

GnomAD3 genomes AF: 0.00217 AC: 330 AN: 152218 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000700

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00464

Gnomad ASJ AF: 0.00288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00103

Gnomad FIN AF: 0.000188

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00303

Gnomad OTH AF: 0.00287

GnomAD2 exomes AF: 0.00232 AC: 576 AN: 248540 AF XY: 0.00243

Gnomad AFR exome AF: 0.000436

Gnomad AMR exome AF: 0.00267

Gnomad ASJ exome AF: 0.00170

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000232

Gnomad NFE exome AF: 0.00357

Gnomad OTH exome AF: 0.00165

GnomAD4 exome AF: 0.00337 AC: 4909 AN: 1458208 Hom.: 16 Cov.: 33 AF XY: 0.00329 AC XY: 2388 AN XY: 725404

African (AFR) AF: 0.000569 AC: 19 AN: 33404

American (AMR) AF: 0.00295 AC: 132 AN: 44708

Ashkenazi Jewish (ASJ) AF: 0.00172 AC: 45 AN: 26124

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39696

South Asian (SAS) AF: 0.00157 AC: 135 AN: 86162

European-Finnish (FIN) AF: 0.000192 AC: 10 AN: 52094

Middle Eastern (MID) AF: 0.00121 AC: 5 AN: 4136

European-Non Finnish (NFE) AF: 0.00395 AC: 4390 AN: 1111704

Other (OTH) AF: 0.00286 AC: 172 AN: 60180

GnomAD4 genome AF: 0.00217 AC: 330 AN: 152336 Hom.: 0 Cov.: 33 AF XY: 0.00192 AC XY: 143 AN XY: 74486

African (AFR) AF: 0.000697 AC: 29 AN: 41580

American (AMR) AF: 0.00464 AC: 71 AN: 15312

Ashkenazi Jewish (ASJ) AF: 0.00288 AC: 10 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5172

South Asian (SAS) AF: 0.00103 AC: 5 AN: 4834

European-Finnish (FIN) AF: 0.000188 AC: 2 AN: 10626

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.00303 AC: 206 AN: 68022

Other (OTH) AF: 0.00284 AC: 6 AN: 2114

Alfa AF: 0.00261 Hom.: 0

Bravo AF: 0.00274

ESP6500AA AF: 0.000684 AC: 3

ESP6500EA AF: 0.00280 AC: 24

ExAC AF: 0.00217 AC: 262

Asia WGS AF: 0.00115 AC: 4 AN: 3478

EpiCase AF: 0.00387

EpiControl AF: 0.00492

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	1	1	Polycystic kidney disease, adult type (2)
-	-	1	not specified (1)
1	-	-	PKD1-Biallelic Autosomal Recessive Polycystic Kidney Disease (1)
-	1	-	PKD1-related disorder (1)
-	-	1	Polycystic kidney disease (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.21
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Uncertain	0.060
CADD	Uncertain	26
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.43	T
Eigen	Uncertain	0.55
Eigen_PC	Uncertain	0.47
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Uncertain	0.90	D
M_CAP	Pathogenic	0.93	D
MetaRNN	Benign	0.19	T
MetaSVM	Uncertain	0.11	D
MutationAssessor	Uncertain	2.6	M
PhyloP100		4.0
PrimateAI	Uncertain	0.62	T
PROVEAN	Uncertain	-3.0	D
REVEL	Uncertain	0.58
Sift	Uncertain	0.0030	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.90
MVP		0.90
ClinPred		0.012	T
GERP RS		5.3
Varity_R		0.20
gMVP		0.56
Mutation Taster		=45/55	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: rs139971481; hg19: chr16-2158419;