16-2104639-G-A

Variant names:

• chr16-2104639-G-A
• rs144557371
• NM_001009944.3:c.8020C>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.8020C>T​(p.Pro2674Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0133 in 1,514,628 control chromosomes in the GnomAD database, including 176 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.011 (16 hom., cov: 19)
  • Exomes 𝑓: 0.014 (160 hom.)
• Consequence: PKD1 NM_001009944.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:13
• Conservation: PhyloP100: 0.911
• 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: 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0047415793).
• BP6: Variant 16-2104639-G-A is Benign according to our data. Variant chr16-2104639-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 257009.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 = 0.0109 (1574/144690) while in subpopulation NFE AF = 0.0161 (1066/66028). AF 95% confidence interval is 0.0153. There are 16 homozygotes in GnomAd4. There are 736 alleles in the male GnomAd4 subpopulation. Median coverage is 19. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 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.8020C>T	p.Pro2674Ser	missense	Exon 22 of 46	NP_001009944.3
	PKD1	NM_000296.4		c.8020C>T	p.Pro2674Ser	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.8020C>T	p.Pro2674Ser	missense	Exon 22 of 46	ENSP00000262304.4
	PKD1	ENST00000423118.5	TSL:1	c.8020C>T	p.Pro2674Ser	missense	Exon 22 of 46	ENSP00000399501.1
	PKD1	ENST00000567946.1	TSL:5	c.79C>T	p.Pro27Ser	missense	Exon 2 of 12	ENSP00000457984.1

Frequencies

GnomAD3 genomes AF: 0.0109 AC: 1573 AN: 144572 Hom.: 16 Cov.: 19

Gnomad AFR AF: 0.00209

Gnomad AMI AF: 0.00222

Gnomad AMR AF: 0.00560

Gnomad ASJ AF: 0.00560

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000682

Gnomad FIN AF: 0.0309

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0161

Gnomad OTH AF: 0.00507

GnomAD2 exomes AF: 0.00937 AC: 1214 AN: 129502 AF XY: 0.00910

Gnomad AFR exome AF: 0.00149

Gnomad AMR exome AF: 0.00645

Gnomad ASJ exome AF: 0.00783

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0311

Gnomad NFE exome AF: 0.0150

Gnomad OTH exome AF: 0.0110

GnomAD4 exome AF: 0.0136 AC: 18586 AN: 1369938 Hom.: 160 Cov.: 23 AF XY: 0.0134 AC XY: 9156 AN XY: 684118

African (AFR) AF: 0.00171 AC: 54 AN: 31500

American (AMR) AF: 0.00609 AC: 261 AN: 42824

Ashkenazi Jewish (ASJ) AF: 0.00733 AC: 185 AN: 25252

East Asian (EAS) AF: 0.0000257 AC: 1 AN: 38836

South Asian (SAS) AF: 0.000994 AC: 82 AN: 82488

European-Finnish (FIN) AF: 0.0293 AC: 1290 AN: 44032

Middle Eastern (MID) AF: 0.000750 AC: 3 AN: 4000

European-Non Finnish (NFE) AF: 0.0154 AC: 16111 AN: 1043822

Other (OTH) AF: 0.0105 AC: 599 AN: 57184

GnomAD4 genome AF: 0.0109 AC: 1574 AN: 144690 Hom.: 16 Cov.: 19 AF XY: 0.0105 AC XY: 736 AN XY: 70198

African (AFR) AF: 0.00208 AC: 80 AN: 38468

American (AMR) AF: 0.00559 AC: 81 AN: 14490

Ashkenazi Jewish (ASJ) AF: 0.00560 AC: 19 AN: 3394

East Asian (EAS) AF: 0.00 AC: 0 AN: 4592

South Asian (SAS) AF: 0.000682 AC: 3 AN: 4396

European-Finnish (FIN) AF: 0.0309 AC: 313 AN: 10144

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 282

European-Non Finnish (NFE) AF: 0.0161 AC: 1066 AN: 66028

Other (OTH) AF: 0.00501 AC: 10 AN: 1996

Alfa AF: 0.0114 Hom.: 4

Bravo AF: 0.00849

ESP6500AA AF: 0.00137 AC: 4

ESP6500EA AF: 0.00786 AC: 49

ExAC AF: 0.00321 AC: 228

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.081
BayesDel_addAF	Benign	-0.57	T
BayesDel_noAF	Benign	-0.58
CADD	Benign	9.5
DANN	Benign	0.75
DEOGEN2	Benign	0.13	T
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.18	N
LIST_S2	Benign	0.66	T
MetaRNN	Benign	0.0047	T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	-2.2	N
PhyloP100		0.91
PrimateAI	Benign	0.32	T
PROVEAN	Benign	0.050	N
REVEL	Benign	0.050
Sift	Benign	0.59	T
Sift4G	Benign	0.73	T
Polyphen		0.0010	B
Vest4		0.11
MVP		0.42
ClinPred		0.0013	T
GERP RS		-2.5
Varity_R		0.034
gMVP		0.17
Mutation Taster		=81/19	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.11		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: rs144557371; hg19: chr16-2154640; COSMIC: COSV99032386; COSMIC: COSV99032386;