rs183084156

chr16-2103613-G-A

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 2P and 16B. PM1 BP4_Strong BP6_Very_Strong BS2

The NM_001009944.3(PKD1):c.8444C>T(p.Ala2815Val) variant causes a missense change. The variant allele was found at a frequency of 0.000187 in 1,610,480 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00025 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00018 (0 hom.)
• Consequence: PKD1 NM_001009944.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 4.06

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 -14 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 5 uncertain in NM_001009944.3
• BP4: Computational evidence support a benign effect (MetaRNN=0.0144970715).
• BP6: Variant 16-2103613-G-A is Benign according to our data. Variant chr16-2103613-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 448018.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2103613-G-A is described in Lovd as [Likely_benign].
• BS2: High AC in GnomAd at 38 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PKD1	NM_001009944.3	c.8444C>T	p.Ala2815Val	missense_variant	23/46	ENST00000262304.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PKD1	ENST00000262304.9	c.8444C>T	p.Ala2815Val	missense_variant	23/46	1	NM_001009944.3	P5

Frequencies

GnomAD3 genomes AF: 0.000250 AC: 38 AN: 152206 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000327

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00620

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000494 AC: 123 AN: 248884 Hom.: 0 AF XY: 0.000406 AC XY: 55 AN XY: 135316

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00654

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000179

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000180 AC: 263 AN: 1458156 Hom.: 0 Cov.: 34 AF XY: 0.000171 AC XY: 124 AN XY: 725396

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00552

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000288

Gnomad4 OTH exome AF: 0.000166

GnomAD4 genome AF: 0.000249 AC: 38 AN: 152324 Hom.: 0 Cov.: 31 AF XY: 0.000228 AC XY: 17 AN XY: 74478

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.000327

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00621

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.0000481 Hom.: 0

Bravo AF: 0.000200

ExAC AF: 0.000515 AC: 62

EpiCase AF: 0.00

EpiControl AF: 0.000178

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Athena Diagnostics

May 03, 2017

- -

Polycystic kidney disease Benign:1

Likely benign, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

-

The PKD1 p.Ala2815Val variant was identified in 3 of 430 proband chromosomes (frequency: 0.007) from individuals or families with ADPKD and was present in 3 of 500 control chromosomes (frequency: 0.006) from healthy individuals (Hirota 2016, Yu 2011). The variant was also identified in dbSNP (ID: rs183084156) as "With Benign allele", ClinVar (classified as benign by Athena Diagnostics), and in ADPKD Mutation Database (as likely neutral). The variant was not identified in LOVD 3.0 or PKD1-LOVD. The variant was identified in control databases in 123 of 275604 chromosomes at a frequency of 0.0005 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: Other in 1 of 6432 chromosomes (freq: 0.0002), European in 2 of 125478 chromosomes (freq: 0.00002), East Asian in 119 of 18844 chromosomes (freq: 0.006), and South Asian in 1 of 30774 chromosomes (freq: 0.00003), but was not observed in the African, Latino, Ashkenazi Jewish, and Finnish, populations. In addition we cannot be certain that data from control databases is specific to PKD1 and not from one of the six PKD1 pseudogenes. The variant was also identified in two cases with a co-occurring pathogenic PKD1 variant (c.856_862del p.Gly287* and c.8470C>T p.Gln2824*) in our laboratory and with PKD1 variant (c.12444G>A Glu4148fs, Yu 2014), increasing the likelihood that the p.Ala2815Val variant does not have clinical significance. The p.Ala2815 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. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign. -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Apr 15, 2020

This variant is associated with the following publications: (PMID: 31730820, 24575920, 22185115, 31030424, 27567292) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.52	T
BayesDel_noAF	Benign	-0.51
Cadd	Benign	16
Dann	Uncertain	0.99
DEOGEN2	Benign	0.23	T;.
Eigen	Benign	-0.11
Eigen_PC	Benign	0.0036
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Benign	0.74	T;T
MetaRNN	Benign	0.014	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.7	L;L
MutationTaster	Benign	0.90	N;N
PrimateAI	Benign	0.42	T
PROVEAN	Benign	-1.3	N;N
REVEL	Benign	0.054
Sift	Benign	0.20	T;T
Sift4G	Uncertain	0.021	D;D
Polyphen		0.021	B;B
Vest4		0.34
MVP		0.65
ClinPred		0.057	T
GERP RS		3.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.090
gMVP		0.48

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: rs183084156; hg19: chr16-2153614;