rs7194935

Positions:

• chr16-2097356-G-A

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The ENST00000262304.9(PKD1):​c.10368C>T​(p.Ala3456=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00563 in 1,612,382 control chromosomes in the GnomAD database, including 402 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.029 (240 hom., cov: 33)
  • Exomes 𝑓: 0.0032 (162 hom.)
• Consequence: PKD1 ENST00000262304.9 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.375

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]

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.62).
• BP6: Variant 16-2097356-G-A is Benign according to our data. Variant chr16-2097356-G-A is described in ClinVar as [Benign]. Clinvar id is 256889.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2097356-G-A is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=-0.375 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.098 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PKD1	NM_001009944.3	c.10368C>T	p.Ala3456=	synonymous_variant	33/46	ENST00000262304.9	NP_001009944.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PKD1	ENST00000262304.9	c.10368C>T	p.Ala3456=	synonymous_variant	33/46	1	NM_001009944.3	ENSP00000262304	P5
PKD1	ENST00000423118.5	c.10365C>T	p.Ala3455=	synonymous_variant	33/46	1		ENSP00000399501	A2
PKD1	ENST00000487932.5	c.*1561C>T		3_prime_UTR_variant, NMD_transcript_variant	20/30	5		ENSP00000457132

Frequencies

GnomAD3 genomes AF: 0.0292 AC: 4437 AN: 152184 Hom.: 238 Cov.: 33

Gnomad AFR AF: 0.100

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0113

Gnomad ASJ AF: 0.00749

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.000515

Gnomad OTH AF: 0.0215

GnomAD3 exomes AF: 0.00770 AC: 1903 AN: 247168 Hom.: 80 AF XY: 0.00572 AC XY: 770 AN XY: 134592

Gnomad AFR exome AF: 0.0990

Gnomad AMR exome AF: 0.00566

Gnomad ASJ exome AF: 0.00543

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000196

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000495

Gnomad OTH exome AF: 0.00578

GnomAD4 exome AF: 0.00316 AC: 4616 AN: 1460080 Hom.: 162 Cov.: 33 AF XY: 0.00275 AC XY: 1998 AN XY: 726380

Gnomad4 AFR exome AF: 0.0991

Gnomad4 AMR exome AF: 0.00608

Gnomad4 ASJ exome AF: 0.00708

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000197

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000335

Gnomad4 OTH exome AF: 0.00704

GnomAD4 genome AF: 0.0293 AC: 4460 AN: 152302 Hom.: 240 Cov.: 33 AF XY: 0.0290 AC XY: 2160 AN XY: 74468

Gnomad4 AFR AF: 0.101

Gnomad4 AMR AF: 0.0112

Gnomad4 ASJ AF: 0.00749

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000515

Gnomad4 OTH AF: 0.0213

Alfa AF: 0.0192 Hom.: 66

Bravo AF: 0.0328

Asia WGS AF: 0.00375 AC: 14 AN: 3478

EpiCase AF: 0.000491

EpiControl AF: 0.000296

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 28, 2020	This variant is associated with the following publications: (PMID: 22008521) -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

-

- -

Polycystic kidney disease, adult type Benign:1

Benign, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Jan 28, 2020

- -

Polycystic kidney disease Benign:1

Benign, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

-

The PKD1 p.Ala3456Ala variant was identified in 4 of 534 proband chromosomes (frequency: 0.007) from individuals or families with ADPKD or renal disease, and was not identified in 100 control chromosomes from healthy individuals (Bataille 2011, Rossetti 2012). These studies have both identified the variant as a polymorphism. The p.Ala3456Ala variant was identified in the dbSNP (ID: rs7194935) with “With Benign allele” with a minor allele frequency of 0.03 (152 of 5000 chromosomes in 1000 Genome Project). In the NHLBI Exome Sequencing Project (Exome Variant Server), the variant was identified in 5 of 8594 alleles (frequency: 0.0005) in the European Americans and 423 of 4392 alleles in African Americans (Frequency: 0.1). The variant was identified in the Exome Aggregation Consortium database (August 08, 2016) in 1034 of 114508 chromosomes (frequency: 0.009 with 45 homozygotes) in the following populations: African in 933of 9530 chromosomes (frequency: 0.1), Latino in 53 of 11138 chromosomes (frequency: 0.005), European (Non-Finnish) in 40 of 62920 chromosomes (frequency: 0.0006), South Asian in 3 of 16084 chromosomes (frequency: 0.0002) and Other in 5 of 820 chromosomes (frequency 0.006) but was not seen in East Asian and Finnish populations, increasing the likelihood this could be a low frequency benign variant. The p.Ala3456Ala variant is not expected to have clinical significance because it does not result in a change of amino acid. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. In summary, based on the above information, this variant meets our laboratory criteria to be classified as benign. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.62
CADD	Benign	0.73
DANN	Benign	0.76
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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: rs7194935; hg19: chr16-2147357;