rs886038369

Positions:

• chr16-2135508-G-A

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Moderate BP6_Very_Strong BS2

The ENST00000262304.9(PKD1):​c.182C>T​(p.Pro61Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00104 in 1,170,080 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00060 (0 hom., cov: 31)
  • Exomes 𝑓: 0.0011 (1 hom.)
• Consequence: PKD1 ENST00000262304.9 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.636

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.

• BP4: Computational evidence support a benign effect (MetaRNN=0.19904986).
• BP6: Variant 16-2135508-G-A is Benign according to our data. Variant chr16-2135508-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 256928.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2135508-G-A is described in Lovd as [Likely_benign].
• BS2: High AC in GnomAd4 at 91 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PKD1	NM_001009944.3	c.182C>T	p.Pro61Leu	missense_variant	1/46	ENST00000262304.9	NP_001009944.3
PKD1	NM_000296.4	c.182C>T	p.Pro61Leu	missense_variant	1/46		NP_000287.4
PKD1	XM_047434208.1	c.182C>T	p.Pro61Leu	missense_variant	1/48		XP_047290164.1
PKD1	XM_047434209.1	c.182C>T	p.Pro61Leu	missense_variant	1/47		XP_047290165.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PKD1	ENST00000262304.9	c.182C>T	p.Pro61Leu	missense_variant	1/46	1	NM_001009944.3	ENSP00000262304	P5
PKD1	ENST00000423118.5	c.182C>T	p.Pro61Leu	missense_variant	1/46	1		ENSP00000399501	A2

Frequencies

GnomAD3 genomes AF: 0.000603 AC: 91 AN: 151034 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.000266

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000983

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00117

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00111 AC: 1130 AN: 1019046 Hom.: 1 Cov.: 22 AF XY: 0.00112 AC XY: 537 AN XY: 479718

Gnomad4 AFR exome AF: 0.0000965

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00125

Gnomad4 OTH exome AF: 0.000688

GnomAD4 genome AF: 0.000603 AC: 91 AN: 151034 Hom.: 0 Cov.: 31 AF XY: 0.000597 AC XY: 44 AN XY: 73736

Gnomad4 AFR AF: 0.000266

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0000983

Gnomad4 NFE AF: 0.00117

Gnomad4 OTH AF: 0.00

Alfa AF: 0.00121 Hom.: 0

Bravo AF: 0.000661

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Mar 02, 2018	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 10, 2019	In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 11967008, 18837007, 30792735) -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

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- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.24
BayesDel_addAF	Benign	-0.31	T
BayesDel_noAF	Benign	-0.31
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.21	T;.
Eigen	Benign	-0.21
Eigen_PC	Benign	-0.27
FATHMM_MKL	Benign	0.71	D
LIST_S2	Benign	0.66	T;T
M_CAP	Pathogenic	0.62	D
MetaRNN	Benign	0.20	T;T
MetaSVM	Benign	-0.90	T
MutationAssessor	Benign	0.69	N;N
MutationTaster	Benign	0.55	D;D
PrimateAI	Uncertain	0.78	T
PROVEAN	Benign	-1.3	N;N
REVEL	Benign	0.080
Sift	Uncertain	0.010	D;D
Sift4G	Uncertain	0.026	D;D
Polyphen		0.92	P;P
Vest4		0.23
MVP		0.67
ClinPred		0.39	T
GERP RS		2.1
Varity_R		0.091
gMVP		0.33

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: rs886038369; hg19: chr16-2185509;