rs763021570

chr16-2114757-C-T

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_001009944.3(PKD1):c.2266G>A(p.Ala756Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000179 in 1,461,146 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0010 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000083 (0 hom.)
• Consequence: PKD1 NM_001009944.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -2.26

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 -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0038975477).
• BP6: Variant 16-2114757-C-T is Benign according to our data. Variant chr16-2114757-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 586257.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomAd at 150 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PKD1	NM_001009944.3	c.2266G>A	p.Ala756Thr	missense_variant	11/46	ENST00000262304.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PKD1	ENST00000262304.9	c.2266G>A	p.Ala756Thr	missense_variant	11/46	1	NM_001009944.3	P5
PKD1	ENST00000423118.5	c.2266G>A	p.Ala756Thr	missense_variant	11/46	1		A2
PKD1	ENST00000488185.2	c.472+2732G>A		intron_variant		5
PKD1	ENST00000568591.5	c.*594G>A		3_prime_UTR_variant, NMD_transcript_variant	7/12	2

Frequencies

GnomAD3 genomes AF: 0.000986 AC: 150 AN: 152138 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00347

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000393

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000165 AC: 22 AN: 133160 Hom.: 0 AF XY: 0.000124 AC XY: 9 AN XY: 72290

Gnomad AFR exome AF: 0.00264

Gnomad AMR exome AF: 0.000206

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000825 AC: 108 AN: 1308892 Hom.: 0 Cov.: 22 AF XY: 0.0000663 AC XY: 43 AN XY: 648980

Gnomad4 AFR exome AF: 0.00307

Gnomad4 AMR exome AF: 0.000169

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: 9.87e-7

Gnomad4 OTH exome AF: 0.000163

GnomAD4 genome AF: 0.00100 AC: 153 AN: 152254 Hom.: 0 Cov.: 32 AF XY: 0.00109 AC XY: 81 AN XY: 74440

Gnomad4 AFR AF: 0.00354

Gnomad4 AMR AF: 0.000392

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000569 Hom.: 0

Bravo AF: 0.00112

ExAC AF: 0.0000905 AC: 2

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Athena Diagnostics

Nov 01, 2017

- -

PKD1-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Dec 08, 2020

This variant is classified as likely 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	0.075
BayesDel_addAF	Benign	-0.71	T
BayesDel_noAF	Benign	-0.79
Cadd	Benign	0.010
Dann	Benign	0.81
DEOGEN2	Benign	0.20	T;.
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.7
FATHMM_MKL	Benign	0.037	N
LIST_S2	Benign	0.54	T;T
M_CAP	Benign	0.029	D
MetaRNN	Benign	0.0039	T;T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	0.065	N;N
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.41	T
PROVEAN	Benign	-0.88	N;N
REVEL	Benign	0.026
Sift	Benign	0.53	T;T
Sift4G	Benign	0.29	T;T
Polyphen		0.0060	B;B
Vest4		0.016
MutPred		0.40		Gain of catalytic residue at A756 (P = 0.0151);Gain of catalytic residue at A756 (P = 0.0151);
MVP		0.41
ClinPred		0.015	T
GERP RS		-7.5
Varity_R		0.031
gMVP		0.19

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: rs763021570; hg19: chr16-2164758;