rs147350387

Variant names:

• chr16-2104536-G-A
• rs147350387
• NM_001009944.3:c.8123C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001009944.3(PKD1):​c.8123C>T​(p.Thr2708Met) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0154 in 1,573,306 control chromosomes in the GnomAD database, including 229 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. T2708T) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.011 (19 hom., cov: 20)
  • Exomes 𝑓: 0.016 (210 hom.)
• Consequence: PKD1 NM_001009944.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:12
• Conservation: PhyloP100: 9.37
• Publications: 15 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.011215836).
• BP6: Variant 16-2104536-G-A is Benign according to our data. Variant chr16-2104536-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 257011.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0114 (1709/150234) while in subpopulation NFE AF = 0.0188 (1268/67612). AF 95% confidence interval is 0.0179. There are 19 homozygotes in GnomAd4. There are 755 alleles in the male GnomAd4 subpopulation. Median coverage is 20. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 19 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.8123C>T	p.Thr2708Met	missense	Exon 22 of 46	NP_001009944.3	P98161-1
	PKD1	NM_000296.4		c.8123C>T	p.Thr2708Met	missense	Exon 22 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.8123C>T	p.Thr2708Met	missense	Exon 22 of 46	ENSP00000262304.4	P98161-1
	PKD1	ENST00000423118.5	TSL:1	c.8123C>T	p.Thr2708Met	missense	Exon 22 of 46	ENSP00000399501.1	P98161-3
	PKD1	ENST00000567946.1	TSL:5	c.182C>T	p.Thr61Met	missense	Exon 2 of 12	ENSP00000457984.1	H3BV77

Frequencies

GnomAD3 genomes AF: 0.0114 AC: 1710 AN: 150116 Hom.: 19 Cov.: 20

Gnomad AFR AF: 0.00300

Gnomad AMI AF: 0.00220

Gnomad AMR AF: 0.0107

Gnomad ASJ AF: 0.00434

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00106

Gnomad FIN AF: 0.0112

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0188

Gnomad OTH AF: 0.00869

GnomAD2 exomes AF: 0.00968 AC: 1474 AN: 152302 AF XY: 0.00986

Gnomad AFR exome AF: 0.00243

Gnomad AMR exome AF: 0.00704

Gnomad ASJ exome AF: 0.00453

Gnomad EAS exome AF: 0.000338

Gnomad FIN exome AF: 0.0109

Gnomad NFE exome AF: 0.0174

Gnomad OTH exome AF: 0.00919

GnomAD4 exome AF: 0.0158 AC: 22553 AN: 1423072 Hom.: 210 Cov.: 30 AF XY: 0.0155 AC XY: 10936 AN XY: 706240

African (AFR) AF: 0.00299 AC: 98 AN: 32736

American (AMR) AF: 0.00655 AC: 270 AN: 41216

Ashkenazi Jewish (ASJ) AF: 0.00454 AC: 116 AN: 25526

East Asian (EAS) AF: 0.000207 AC: 8 AN: 38692

South Asian (SAS) AF: 0.00133 AC: 110 AN: 82414

European-Finnish (FIN) AF: 0.0138 AC: 669 AN: 48330

Middle Eastern (MID) AF: 0.00195 AC: 8 AN: 4102

European-Non Finnish (NFE) AF: 0.0188 AC: 20491 AN: 1091236

Other (OTH) AF: 0.0133 AC: 783 AN: 58820

GnomAD4 genome AF: 0.0114 AC: 1709 AN: 150234 Hom.: 19 Cov.: 20 AF XY: 0.0103 AC XY: 755 AN XY: 73348

African (AFR) AF: 0.00299 AC: 121 AN: 40496

American (AMR) AF: 0.0107 AC: 162 AN: 15142

Ashkenazi Jewish (ASJ) AF: 0.00434 AC: 15 AN: 3454

East Asian (EAS) AF: 0.00 AC: 0 AN: 4962

South Asian (SAS) AF: 0.00106 AC: 5 AN: 4732

European-Finnish (FIN) AF: 0.0112 AC: 118 AN: 10538

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

European-Non Finnish (NFE) AF: 0.0188 AC: 1268 AN: 67612

Other (OTH) AF: 0.00860 AC: 18 AN: 2094

Alfa AF: 0.0148 Hom.: 7

Bravo AF: 0.0104

ESP6500AA AF: 0.00269 AC: 11

ESP6500EA AF: 0.0158 AC: 129

ExAC AF: 0.00428 AC: 462

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not provided (5)
-	-	2	not specified (2)
-	-	2	Polycystic kidney disease, adult type (2)
-	-	1	Autosomal dominant 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	0.29
BayesDel_addAF	Benign	-0.27	T
BayesDel_noAF	Benign	-0.14
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.73	D
Eigen	Uncertain	0.47
Eigen_PC	Uncertain	0.33
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.89	D
MetaRNN	Benign	0.011	T
MetaSVM	Benign	-0.63	T
MutationAssessor	Uncertain	2.8	M
PhyloP100		9.4
PrimateAI	Uncertain	0.59	T
PROVEAN	Uncertain	-3.4	D
REVEL	Uncertain	0.39
Sift	Uncertain	0.0010	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.59
MVP		0.78
ClinPred		0.016	T
GERP RS		4.2
Varity_R		0.40
gMVP		0.71
Mutation Taster		=80/20	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: rs147350387; hg19: chr16-2154537; COSMIC: COSV99032379; COSMIC: COSV99032379;