16-2111152-C-T

Position:

• chr16-2111152-C-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 0P and 2B. BP4 BS2_Supporting

The NM_001009944.3(PKD1):​c.4015G>A​(p.Val1339Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000245 in 1,611,168 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.00025 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00024 (0 hom.)
• Consequence: PKD1 NM_001009944.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:4
• Conservation: PhyloP100: -1.07

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 Likely_benign. Variant got -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.36888236).
• BS2: High AC in GnomAd4 at 38 AD gene. Variant has AC lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PKD1	NM_001009944.3	c.4015G>A	p.Val1339Met	missense_variant	15/46	ENST00000262304.9	NP_001009944.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PKD1	ENST00000262304.9	c.4015G>A	p.Val1339Met	missense_variant	15/46	1	NM_001009944.3	ENSP00000262304	P5

Frequencies

GnomAD3 genomes AF: 0.000250 AC: 38 AN: 152214 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000965

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000577

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000188

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000367

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000207 AC: 51 AN: 246616 Hom.: 0 AF XY: 0.000245 AC XY: 33 AN XY: 134540

Gnomad AFR exome AF: 0.0000640

Gnomad AMR exome AF: 0.0000581

Gnomad ASJ exome AF: 0.000201

Gnomad EAS exome AF: 0.0000557

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.000140

Gnomad NFE exome AF: 0.000380

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000244 AC: 356 AN: 1458836 Hom.: 0 Cov.: 36 AF XY: 0.000223 AC XY: 162 AN XY: 725790

Gnomad4 AFR exome AF: 0.0000898

Gnomad4 AMR exome AF: 0.000112

Gnomad4 ASJ exome AF: 0.000115

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.000154

Gnomad4 NFE exome AF: 0.000285

Gnomad4 OTH exome AF: 0.000282

GnomAD4 genome AF: 0.000249 AC: 38 AN: 152332 Hom.: 0 Cov.: 33 AF XY: 0.000269 AC XY: 20 AN XY: 74484

Gnomad4 AFR AF: 0.0000962

Gnomad4 AMR AF: 0.000196

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000579

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000188

Gnomad4 NFE AF: 0.000368

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.000248 Hom.: 0

Bravo AF: 0.000268

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000466 AC: 4

ExAC AF: 0.000166 AC: 20

EpiCase AF: 0.000327

EpiControl AF: 0.000237

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2024	PKD1: PM2, BP4 -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Apr 12, 2023	In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Polycystic kidney disease, adult type Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 31, 2018

- -

Polycystic kidney disease Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

-

The PKD1 p.Val1339Met variant was not identified in the literature nor was it identified in the Clinvitae, ClinVar, MutDB, GeneInsight COGR, PKD1-LOVD and PKD1-LOVD 3.0 databases. The variant was identified in dbSNP (ID: rs147141131) as “NA”; NHLBI GO Exome Sequencing Project in 4 of 8584 European American and not found in African American alleles. The variant was identified in Exome Aggregation Consortium database (March 14, 2016) in 20 of 116858 chromosomes (freq. 0.0001711) in the following populations: European (Non-Finnish) in 18 of 63996 chromosomes (freq. 0.0002813), East Asian in 1 of 8490 chromosomes (freq. 0.0001178), African in 1 of 9514 chromosomes (freq. 0.0001051), but was not seen in European (Finnish), Latino, South Asian and Other populations, increasing the likelihood this could be a low frequency benign variant. 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 ADPKD Mutation Database (classified as Likely Neutral and found with truncating variants and other more likely pathogenic missense mutations). The p.Val1339 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein. The variant occurs outside of the splicing consensus sequence and 3 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict a greater than 10% difference splicing; a loss of a predicted splice site at a non-consensus splicing location. However, this information is not predictive enough to assume pathogenicity. In summary, based on the above information, the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.38	T
BayesDel_noAF	Benign	-0.48
CADD	Benign	12
DANN	Uncertain	0.99
DEOGEN2	Benign	0.25	T;.
Eigen	Benign	-0.55
Eigen_PC	Benign	-0.77
FATHMM_MKL	Benign	0.040	N
LIST_S2	Uncertain	0.88	D;D
M_CAP	Pathogenic	0.81	D
MetaRNN	Benign	0.37	T;T
MetaSVM	Benign	-0.72	T
MutationAssessor	Uncertain	2.4	M;M
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.32	T
PROVEAN	Benign	-1.2	N;N
REVEL	Benign	0.13
Sift	Benign	0.076	T;T
Sift4G	Uncertain	0.028	D;D
Polyphen		0.98	D;D
Vest4		0.36
MVP		0.69
ClinPred		0.16	T
GERP RS		-0.24
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.042
gMVP		0.38

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: rs147141131; hg19: chr16-2161153;