rs13337123

Variant names:

• chr16-2102864-C-G
• rs13337123
• NM_001009944.3:c.8898G>C

Your query was ambiguous. Multiple possible variants found:

• chr16-2102864-C-G
• chr16-2102864-C-A
• chr16-2102864-C-T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001009944.3(PKD1):​c.8898G>C​(p.Glu2966Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0088 in 1,594,798 control chromosomes in the GnomAD database, including 1,046 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E2966Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.052 (547 hom., cov: 32)
  • Exomes 𝑓: 0.0047 (499 hom.)
• Consequence: PKD1 NM_001009944.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 0.628
• Publications: 11 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=0.002373308).
• BP6: Variant 16-2102864-C-G is Benign according to our data. Variant chr16-2102864-C-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 257030.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.175 is higher than 0.05.

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.8898G>C	p.Glu2966Asp	missense	Exon 24 of 46	NP_001009944.3	P98161-1
	PKD1	NM_000296.4		c.8898G>C	p.Glu2966Asp	missense	Exon 24 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.8898G>C	p.Glu2966Asp	missense	Exon 24 of 46	ENSP00000262304.4	P98161-1
	PKD1	ENST00000423118.5	TSL:1	c.8898G>C	p.Glu2966Asp	missense	Exon 24 of 46	ENSP00000399501.1	P98161-3
	PKD1	ENST00000480227.5	TSL:1	n.635G>C		non_coding_transcript_exon	Exon 2 of 8

Frequencies

GnomAD3 genomes AF: 0.0517 AC: 7124 AN: 137814 Hom.: 547 Cov.: 32

Gnomad AFR AF: 0.179

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0240

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00119

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0145

Gnomad NFE AF: 0.000503

Gnomad OTH AF: 0.0402

GnomAD2 exomes AF: 0.0124 AC: 3076 AN: 248986 AF XY: 0.00895

Gnomad AFR exome AF: 0.166

Gnomad AMR exome AF: 0.00903

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000428

Gnomad OTH exome AF: 0.00427

GnomAD4 exome AF: 0.00474 AC: 6900 AN: 1456864 Hom.: 499 Cov.: 34 AF XY: 0.00395 AC XY: 2859 AN XY: 724698

African (AFR) AF: 0.163 AC: 5437 AN: 33326

American (AMR) AF: 0.0104 AC: 463 AN: 44480

Ashkenazi Jewish (ASJ) AF: 0.0000383 AC: 1 AN: 26108

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39656

South Asian (SAS) AF: 0.000419 AC: 36 AN: 86010

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51760

Middle Eastern (MID) AF: 0.00654 AC: 27 AN: 4130

European-Non Finnish (NFE) AF: 0.000247 AC: 274 AN: 1111260

Other (OTH) AF: 0.0110 AC: 661 AN: 60134

GnomAD4 genome AF: 0.0517 AC: 7133 AN: 137934 Hom.: 547 Cov.: 32 AF XY: 0.0495 AC XY: 3342 AN XY: 67574

African (AFR) AF: 0.178 AC: 6685 AN: 37490

American (AMR) AF: 0.0240 AC: 334 AN: 13930

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3190

East Asian (EAS) AF: 0.00 AC: 0 AN: 4574

South Asian (SAS) AF: 0.000955 AC: 4 AN: 4190

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 9932

Middle Eastern (MID) AF: 0.0154 AC: 4 AN: 260

European-Non Finnish (NFE) AF: 0.000503 AC: 31 AN: 61660

Other (OTH) AF: 0.0397 AC: 75 AN: 1890

Alfa AF: 0.0116 Hom.: 39

Bravo AF: 0.0537

ESP6500AA AF: 0.156 AC: 686

ESP6500EA AF: 0.000466 AC: 4

ExAC AF: 0.0152 AC: 1837

EpiCase AF: 0.000164

EpiControl AF: 0.000474

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	2	not specified (2)
-	-	1	Autosomal dominant polycystic kidney disease (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	0.13
BayesDel_addAF	Benign	-0.70	T
BayesDel_noAF	Benign	-0.63
CADD	Benign	2.6
DANN	Benign	0.70
DEOGEN2	Benign	0.16	T
Eigen	Benign	-0.49
Eigen_PC	Benign	-0.64
FATHMM_MKL	Benign	0.28	N
LIST_S2	Benign	0.45	T
MetaRNN	Benign	0.0024	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.7	L
PhyloP100		0.63
PrimateAI	Benign	0.34	T
PROVEAN	Benign	-0.53	N
REVEL	Benign	0.029
Sift	Benign	0.29	T
Sift4G	Benign	0.099	T
Polyphen		0.0090	B
Vest4		0.043
MutPred		0.38		Loss of sheet (P = 0.0457)
ClinPred		0.00095	T
GERP RS		2.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.029
gMVP		0.26
Mutation Taster		=63/37	polymorphism (auto)

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: rs13337123; hg19: chr16-2152865;