rs34197769

chr16-2094175-G-A

Variant summary

Our verdict is Benign. Variant got -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. 13/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as 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 criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.536

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

Verdict is Benign. Variant got -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]. Clinvar id is 256893.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2094175-G-A is described in Lovd as [Likely_benign].
• 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/exons	MANE	UniProt
PKD1	NM_001009944.3	c.10535C>T	p.Ala3512Val	missense_variant	35/46	ENST00000262304.9
PKD1-AS1	NR_135175.1	n.304-546G>A		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PKD1	ENST00000262304.9	c.10535C>T	p.Ala3512Val	missense_variant	35/46	1	NM_001009944.3	P5
PKD1-AS1	ENST00000563284.3	n.195-546G>A		intron_variant, non_coding_transcript_variant		3

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

GnomAD3 exomes AF: 0.0726 AC: 16961 AN: 233670 Hom.: 763 AF XY: 0.0722 AC XY: 9205 AN XY: 127414

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 SAS exome AF: 0.0443

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

Gnomad4 AFR exome AF: 0.124

Gnomad4 AMR exome AF: 0.0361

Gnomad4 ASJ exome AF: 0.109

Gnomad4 EAS exome AF: 0.000227

Gnomad4 SAS exome AF: 0.0443

Gnomad4 FIN exome AF: 0.144

Gnomad4 NFE exome AF: 0.0781

Gnomad4 OTH exome AF: 0.0747

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

Gnomad4 AFR AF: 0.129

Gnomad4 AMR AF: 0.0583

Gnomad4 ASJ AF: 0.0979

Gnomad4 EAS AF: 0.000772

Gnomad4 SAS AF: 0.0429

Gnomad4 FIN AF: 0.145

Gnomad4 NFE AF: 0.0774

Gnomad4 OTH AF: 0.0728

Alfa AF: 0.0802 Hom.: 600

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

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Polycystic kidney disease, adult type Benign:2

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	May 15, 2017	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Apr 22, 2020	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

-

- -

Polycystic kidney disease Benign:1

Benign, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

-

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

Benign, criteria provided, single submitter

research

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

Jan 01, 2019

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Oct 03, 2019

- -

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;.
MutationTaster	Benign	1.0	P;P
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

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

Publications

LitVar

Other links and lift over

dbSNP: rs34197769; hg19: chr16-2144176; COSMIC: COSV51916403; COSMIC: COSV51916403;