rs140412120

chr16-2110947-G-A

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_001009944.3(PKD1):c.4220C>T(p.Pro1407Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000571 in 1,610,848 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (no stars). Synonymous variant affecting the same amino acid position (i.e. P1407P) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000098 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000053 (1 hom.)
• Consequence: PKD1 NM_001009944.3 missense
• Clinical Significance: Uncertain significance no assertion criteria provided U:1
• Conservation: PhyloP100: 0.733

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 -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.06226161).
• BS2: High AC in GnomAd at 15 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PKD1	NM_001009944.3	c.4220C>T	p.Pro1407Leu	missense_variant	15/46	ENST00000262304.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PKD1	ENST00000262304.9	c.4220C>T	p.Pro1407Leu	missense_variant	15/46	1	NM_001009944.3	P5

Frequencies

GnomAD3 genomes AF: 0.0000986 AC: 15 AN: 152202 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000121 AC: 30 AN: 247188 Hom.: 0 AF XY: 0.000111 AC XY: 15 AN XY: 134698

Gnomad AFR exome AF: 0.000383

Gnomad AMR exome AF: 0.0000290

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000110

Gnomad SAS exome AF: 0.000196

Gnomad FIN exome AF: 0.0000463

Gnomad NFE exome AF: 0.000108

Gnomad OTH exome AF: 0.000331

GnomAD4 exome AF: 0.0000528 AC: 77 AN: 1458528 Hom.: 1 Cov.: 36 AF XY: 0.0000538 AC XY: 39 AN XY: 725560

Gnomad4 AFR exome AF: 0.000239

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.000232

Gnomad4 FIN exome AF: 0.0000384

Gnomad4 NFE exome AF: 0.0000369

Gnomad4 OTH exome AF: 0.0000498

GnomAD4 genome AF: 0.0000985 AC: 15 AN: 152320 Hom.: 0 Cov.: 33 AF XY: 0.0000671 AC XY: 5 AN XY: 74478

Gnomad4 AFR AF: 0.000241

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000588

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000130 Hom.: 0

Bravo AF: 0.000110

ESP6500AA AF: 0.000456 AC: 2

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000174 AC: 21

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: no assertion criteria provided

Submissions by phenotype

Polycystic kidney disease Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

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The PKD1 p.Pro1407Leu variant was not identified in the literature nor was it identified in the, GeneInsight COGR, Clinvitae, ClinVar, MutDB, ADPKD Mutation, PKD1-LOVD and PKD1-LOVD 3.0 databases. The variant was identified in dbSNP (ID: rs140412120) as “NA”, in the 1000 Genomes Project in 1 of 5000 chromosomes (frequency: 0.0002) and in NHLBI GO Exome Sequencing Project in 2 of 4384 African American alleles (freq. 0.0005). In addition, the variant was identified in the Exome Aggregation Consortium database (August 8, 2016) in 21 of 117852 chromosomes (freq. 0.0002) in the following populations: African in 6 of 9630 chromosomes (freq. 0.0006), East Asian in 2 of 8578 chromosomes (freq. 0.0002), South Asian in 3 of 16502 chromosomes (freq. 0.0002), European (Non-Finnish) in 10 of 64154 chromosomes (freq. 0.0002) but was not seen in European (Finnish) and Latino 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 p.Pro1407 residue is conserved in mammals and four out of five 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, HumanSpliceFinder) 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. This variant is classified as a variant of uncertain significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.075
BayesDel_addAF	Benign	-0.38	T
BayesDel_noAF	Benign	-0.48
Cadd	Benign	3.1
Dann	Benign	0.59
DEOGEN2	Benign	0.23	T;.
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.11	N
LIST_S2	Benign	0.65	T;T
M_CAP	Uncertain	0.20	D
MetaRNN	Benign	0.062	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.1	L;L
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.32	T
PROVEAN	Benign	-1.8	N;N
REVEL	Benign	0.049
Sift	Benign	0.42	T;T
Sift4G	Benign	1.0	T;T
Polyphen		0.021	B;B
Vest4		0.24
MVP		0.44
ClinPred		0.0047	T
GERP RS		2.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.027
gMVP		0.29

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: rs140412120; hg19: chr16-2160948; COSMIC: COSV51927350; COSMIC: COSV51927350;