rs34197769

Variant names:

• chr16-2094175-G-A
• rs34197769
• NM_001009944.3:c.10535C>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.10535C>T​(p.Ala3512Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0778 in 1,603,254 control chromosomes in the GnomAD database, including 5,443 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 (★★). Synonymous variant affecting the same amino acid position (i.e. A3512A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.091 (736 hom., cov: 33)
  • Exomes 𝑓: 0.076 (4707 hom.)
• Consequence: PKD1 NM_001009944.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 0.536
• Publications: 35 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-AS1 (HGNC:56035): (PKD1 antisense RNA 1)

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.002803743).
• BP6: Variant 16-2094175-G-A is Benign according to our data. Variant chr16-2094175-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 256893.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.126 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PKD1	NM_001009944.3	c.10535C>T	p.Ala3512Val	missense_variant	Exon 35 of 46	ENST00000262304.9	NP_001009944.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PKD1	ENST00000262304.9	c.10535C>T	p.Ala3512Val	missense_variant	Exon 35 of 46	1	NM_001009944.3	ENSP00000262304.4

Frequencies

GnomAD3 genomes AF: 0.0905 AC: 13762 AN: 152136 Hom.: 735 Cov.: 33

Gnomad AFR AF: 0.129

Gnomad AMI AF: 0.0143

Gnomad AMR AF: 0.0584

Gnomad ASJ AF: 0.0979

Gnomad EAS AF: 0.000770

Gnomad SAS AF: 0.0433

Gnomad FIN AF: 0.145

Gnomad MID AF: 0.0538

Gnomad NFE AF: 0.0774

Gnomad OTH AF: 0.0735

GnomAD2 exomes AF: 0.0726 AC: 16961 AN: 233670 AF XY: 0.0722

Gnomad AFR exome AF: 0.124

Gnomad AMR exome AF: 0.0345

Gnomad ASJ exome AF: 0.106

Gnomad EAS exome AF: 0.000278

Gnomad FIN exome AF: 0.144

Gnomad NFE exome AF: 0.0811

Gnomad OTH exome AF: 0.0742

GnomAD4 exome AF: 0.0765 AC: 110966 AN: 1451002 Hom.: 4707 Cov.: 30 AF XY: 0.0754 AC XY: 54426 AN XY: 721564

African (AFR) AF: 0.124 AC: 4118 AN: 33304

American (AMR) AF: 0.0361 AC: 1595 AN: 44208

Ashkenazi Jewish (ASJ) AF: 0.109 AC: 2831 AN: 25938

East Asian (EAS) AF: 0.000227 AC: 9 AN: 39582

South Asian (SAS) AF: 0.0443 AC: 3768 AN: 85060

European-Finnish (FIN) AF: 0.144 AC: 7422 AN: 51508

Middle Eastern (MID) AF: 0.0650 AC: 374 AN: 5758

European-Non Finnish (NFE) AF: 0.0781 AC: 86371 AN: 1105660

Other (OTH) AF: 0.0747 AC: 4478 AN: 59984

GnomAD4 genome AF: 0.0905 AC: 13779 AN: 152252 Hom.: 736 Cov.: 33 AF XY: 0.0927 AC XY: 6900 AN XY: 74424

African (AFR) AF: 0.129 AC: 5353 AN: 41542

American (AMR) AF: 0.0583 AC: 892 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.0979 AC: 340 AN: 3472

East Asian (EAS) AF: 0.000772 AC: 4 AN: 5180

South Asian (SAS) AF: 0.0429 AC: 207 AN: 4828

European-Finnish (FIN) AF: 0.145 AC: 1542 AN: 10600

Middle Eastern (MID) AF: 0.0445 AC: 13 AN: 292

European-Non Finnish (NFE) AF: 0.0774 AC: 5261 AN: 68012

Other (OTH) AF: 0.0728 AC: 154 AN: 2116

Alfa AF: 0.0801 Hom.: 894

Bravo AF: 0.0843

TwinsUK AF: 0.0836 AC: 310

ALSPAC AF: 0.0794 AC: 306

ESP6500AA AF: 0.125 AC: 547

ESP6500EA AF: 0.0816 AC: 701

ExAC AF: 0.0728 AC: 8774

Asia WGS AF: 0.0320 AC: 112 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 02, 2025

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Polycystic kidney disease, adult type Benign:2

Apr 22, 2020

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 15, 2017

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Oct 03, 2019

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Polycystic kidney disease Benign:1

-

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

The c.10535C>T, p.Ala3512Val variant was identified in 10.09% of 7978 control alleles in the Exome Aggregation Consortium (March 14, 2016). According to ACMG guidelines for variant classification based on allele frequency, category BA1, this variant is considered benign and has not been further reviewed (Richards 2015). -

Autosomal dominant polycystic kidney disease Benign:1

Jan 01, 2019

Molecular Genetics of Inherited Kidney Disorders Laboratory, Garvan Institute of Medical Research

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: research

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.075
BayesDel_addAF	Benign	-0.77	T
BayesDel_noAF	Benign	-0.77
CADD	Benign	0.74
DANN	Benign	0.43
DEOGEN2	Benign	0.13	T;.
Eigen	Benign	-2.1
Eigen_PC	Benign	-2.2
FATHMM_MKL	Benign	0.0061	N
LIST_S2	Benign	0.46	T;T
MetaRNN	Benign	0.0028	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.69	N;.
PhyloP100		0.54
PrimateAI	Benign	0.22	T
PROVEAN	Benign	-0.13	N;N
REVEL	Benign	0.035
Sift	Benign	1.0	T;T
Sift4G	Benign	0.34	T;T
Polyphen		0.23	B;B
Vest4		0.026
ClinPred		0.012	T
GERP RS		-9.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.018
gMVP		0.22
Mutation Taster		=97/3	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs34197769; hg19: chr16-2144176; COSMIC: COSV51916403; COSMIC: COSV51916403;