rs140980374

Positions:

• chr16-2110903-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001009944.3(PKD1):​c.4264G>A​(p.Ala1422Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00544 in 1,611,388 control chromosomes in the GnomAD database, including 52 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0050 (4 hom., cov: 33)
  • Exomes 𝑓: 0.0055 (48 hom.)
• Consequence: PKD1 NM_001009944.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: -0.0600

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.004206896).
• BP6: Variant 16-2110903-C-T is Benign according to our data. Variant chr16-2110903-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 256964.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2110903-C-T is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population mid. gnomad4_exome allele frequency = 0.00549 (8012/1459086) while in subpopulation MID AF= 0.0489 (233/4762). AF 95% confidence interval is 0.0438. There are 48 homozygotes in gnomad4_exome. There are 3989 alleles in male gnomad4_exome subpopulation. Median coverage is 36. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 758 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PKD1	NM_001009944.3	c.4264G>A	p.Ala1422Thr	missense_variant	15/46	ENST00000262304.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PKD1	ENST00000262304.9	c.4264G>A	p.Ala1422Thr	missense_variant	15/46	1	NM_001009944.3	P5

Frequencies

GnomAD3 genomes AF: 0.00499 AC: 759 AN: 152184 Hom.: 4 Cov.: 33

Gnomad AFR AF: 0.00111

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00661

Gnomad ASJ AF: 0.0343

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00518

Gnomad FIN AF: 0.00113

Gnomad MID AF: 0.0475

Gnomad NFE AF: 0.00613

Gnomad OTH AF: 0.0110

GnomAD3 exomes AF: 0.00591 AC: 1472 AN: 248902 Hom.: 12 AF XY: 0.00603 AC XY: 816 AN XY: 135334

Gnomad AFR exome AF: 0.000627

Gnomad AMR exome AF: 0.00385

Gnomad ASJ exome AF: 0.0337

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00477

Gnomad FIN exome AF: 0.00152

Gnomad NFE exome AF: 0.00673

Gnomad OTH exome AF: 0.0102

GnomAD4 exome AF: 0.00549 AC: 8012 AN: 1459086 Hom.: 48 Cov.: 36 AF XY: 0.00550 AC XY: 3989 AN XY: 725832

Gnomad4 AFR exome AF: 0.00179

Gnomad4 AMR exome AF: 0.00391

Gnomad4 ASJ exome AF: 0.0313

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00428

Gnomad4 FIN exome AF: 0.00150

Gnomad4 NFE exome AF: 0.00521

Gnomad4 OTH exome AF: 0.00802

GnomAD4 genome AF: 0.00498 AC: 758 AN: 152302 Hom.: 4 Cov.: 33 AF XY: 0.00485 AC XY: 361 AN XY: 74462

Gnomad4 AFR AF: 0.00111

Gnomad4 AMR AF: 0.00660

Gnomad4 ASJ AF: 0.0343

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00518

Gnomad4 FIN AF: 0.00113

Gnomad4 NFE AF: 0.00613

Gnomad4 OTH AF: 0.0109

Alfa AF: 0.00753 Hom.: 8

Bravo AF: 0.00506

ESP6500AA AF: 0.00205 AC: 9

ESP6500EA AF: 0.00838 AC: 72

ExAC AF: 0.00593 AC: 717

Asia WGS AF: 0.00289 AC: 10 AN: 3478

EpiCase AF: 0.00872

EpiControl AF: 0.00836

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:4

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 08, 2020	This variant is associated with the following publications: (PMID: 17582161, 22383692) -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2024	PKD1: BP4, BS1, BS2 -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

not specified Benign:1

Benign, no assertion criteria provided

clinical testing

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

-

- -

Polycystic kidney disease, adult type Benign:1

Benign, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Dec 20, 2019

- -

Polycystic kidney disease Benign:1

Benign, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

-

PKD1, EXON15, c.4264G>A, p.Ala1422Thr, (Alias c.4475G>A), Heterozygous, Benign The PKD1 p.Ala1422Thr variant was identified in 3 of 864 proband chromosomes (frequency: 0.003) from individuals or families with ADPKD, and was not identified in 242 control chromosomes from healthy individuals (Rossetti 2007, Rossetti 2012). The variant was also identified in dbSNP (ID: rs140980374) “With clinical significance allele not available”, in 1000 Genomes Project in 22 of 5000 chromosomes (frequency: 0.004), in NHLBI GO Exome Sequencing Project (ESP) in 72 of 8592 European American (frequency: 0.008) and 9 in 4394 (frequency: 0.002) African American alleles. This variant was identified in the Exome Aggregation Consortium database (March 2016) in 713 (5 homozygous) of 118566 chromosomes (freq. 0.006) in the following populations: other in 10 of 880 chromosomes (freq. 0.01), European (Non-Finnish) in 565 of 64594 chromosomes (freq. 0.009), South Asian in 76 of 16504 chromosomes (freq. 0.005), Latino in 45 of 11538 chromosomes (freq. 0.004), Finnish in 7 of 6602 chromosomes (freq. 0.001), and African in 10 of 9854 chromosomes (freq. 0.001), but was not seen in the East Asian populations, increasing the likelihood this could be a low frequency benign variant. However we cannot be certain that variant data from control databases is specific to PKD1 and not from one of the six PKD1 pseudogenes. Furthermore, the variant is listed in the GeneInsight COGR database as benign, as likely neutral in the ADPKD Mutation Database, and listed with no classification in the PKD1-LOVD 3.0 database. The p.Ala1422 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out pathogenicity. Furthermore, the variant amino acid “Threonine” is present in macaque, increasing the likelihood that this variant does not have clinical significance. Computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein. 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. The variant was observed as co-occurring with another pathogenic variant in one individual identified by our laboratory, increasing the likelihood this variant does not have clinical significance. In summary, based on the above information, this variant is classified as benign. -

Autosomal dominant polycystic kidney disease Benign:1

Likely benign, criteria provided, single submitter

research

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

Jan 01, 2019

- -

PKD1-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Sep 05, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.068
BayesDel_addAF	Benign	-0.57	T
BayesDel_noAF	Benign	-0.59
CADD	Benign	0.13
DANN	Benign	0.58
DEOGEN2	Benign	0.15	T;.
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.6
FATHMM_MKL	Benign	0.088	N
LIST_S2	Benign	0.24	T;T
MetaRNN	Benign	0.0042	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.090	N;N
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.31	T
PROVEAN	Benign	0.14	N;N
REVEL	Benign	0.018
Sift	Benign	0.41	T;T
Sift4G	Benign	0.47	T;T
Polyphen		0.083	B;B
Vest4		0.085
MVP		0.55
ClinPred		0.00098	T
GERP RS		-1.8
Varity_R		0.027
gMVP		0.16

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

Publications

LitVar

Other links and lift over

dbSNP: rs140980374; hg19: chr16-2160904;