rs2549677

chr16-2112360-A-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001009944.3(PKD1):c.3275T>C(p.Met1092Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0875 in 1,514,852 control chromosomes in the GnomAD database, including 13,074 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Uncertain significancein ClinVar.

• Frequency:
  • Genomes: 𝑓 0.20 (5154 hom., cov: 33)
  • Exomes 𝑓: 0.075 (7920 hom.)
• Consequence: PKD1 NM_001009944.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 2.85

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]

(HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.020166844).
• BP6: Variant 16-2112360-A-G is Benign according to our data. Variant chr16-2112360-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 256947.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2112360-A-G is described in Lovd as [Likely_benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.457 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PKD1	NM_001009944.3	c.3275T>C	p.Met1092Thr	missense_variant	14/46	ENST00000262304.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PKD1	ENST00000262304.9	c.3275T>C	p.Met1092Thr	missense_variant	14/46	1	NM_001009944.3	P5
	ENST00000568795.1	n.26A>G		non_coding_transcript_exon_variant	1/2	2

Frequencies

GnomAD3 genomes AF: 0.197 AC: 29974 AN: 152056 Hom.: 5135 Cov.: 33

Gnomad AFR AF: 0.462

Gnomad AMI AF: 0.123

Gnomad AMR AF: 0.136

Gnomad ASJ AF: 0.159

Gnomad EAS AF: 0.000578

Gnomad SAS AF: 0.0284

Gnomad FIN AF: 0.0758

Gnomad MID AF: 0.187

Gnomad NFE AF: 0.0991

Gnomad OTH AF: 0.192

GnomAD3 exomes AF: 0.0721 AC: 15410 AN: 213684 Hom.: 1527 AF XY: 0.0656 AC XY: 7765 AN XY: 118316

Gnomad AFR exome AF: 0.397

Gnomad AMR exome AF: 0.0671

Gnomad ASJ exome AF: 0.105

Gnomad EAS exome AF: 0.0000560

Gnomad SAS exome AF: 0.0204

Gnomad FIN exome AF: 0.0399

Gnomad NFE exome AF: 0.0674

Gnomad OTH exome AF: 0.0886

GnomAD4 exome AF: 0.0752 AC: 102537 AN: 1362680 Hom.: 7920 Cov.: 32 AF XY: 0.0729 AC XY: 49520 AN XY: 678960

Gnomad4 AFR exome AF: 0.434

Gnomad4 AMR exome AF: 0.0757

Gnomad4 ASJ exome AF: 0.125

Gnomad4 EAS exome AF: 0.000176

Gnomad4 SAS exome AF: 0.0259

Gnomad4 FIN exome AF: 0.0619

Gnomad4 NFE exome AF: 0.0705

Gnomad4 OTH exome AF: 0.0967

GnomAD4 genome AF: 0.197 AC: 30036 AN: 152172 Hom.: 5154 Cov.: 33 AF XY: 0.190 AC XY: 14124 AN XY: 74428

Gnomad4 AFR AF: 0.462

Gnomad4 AMR AF: 0.136

Gnomad4 ASJ AF: 0.159

Gnomad4 EAS AF: 0.000579

Gnomad4 SAS AF: 0.0280

Gnomad4 FIN AF: 0.0758

Gnomad4 NFE AF: 0.0991

Gnomad4 OTH AF: 0.190

Alfa AF: 0.148 Hom.: 515

Bravo AF: 0.217

ExAC AF: 0.0712 AC: 8153

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Polycystic kidney disease, adult type Benign:2

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jun 05, 2017	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Jul 07, 2020	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

-

- -

Polycystic kidney disease Benign:1

Benign, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

-

The c.3275T>C, p.Met1092Thr variant was identified in 7.5% of 6086 control alleles in the Exome Aggregation Consortium (March 14, 2016). According to ACMG guidelines for variant classification based on allele frequency, category BA1, this variant is considered benign and has not been further reviewed (Richards 2015). -

Autosomal dominant polycystic kidney disease Benign:1

Likely benign, criteria provided, single submitter

research

Molecular Genetics of Inherited Kidney Disorders Laboratory, Garvan Institute of Medical Research

Jan 01, 2019

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Dec 30, 2019

This variant is associated with the following publications: (PMID: 22608885) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.037
BayesDel_addAF	Benign	-0.60	T
BayesDel_noAF	Benign	-0.50
Cadd	Benign	12
Dann	Benign	0.67
DEOGEN2	Benign	0.15	T;.
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.0020	N
LIST_S2	Benign	0.21	T;T
MetaRNN	Benign	0.020	T;T
MetaSVM	Benign	-0.90	T
MutationAssessor	Benign	-2.7	N;N
MutationTaster	Benign	1.0	P;P
PrimateAI	Benign	0.41	T
PROVEAN	Benign	2.5	N;N
REVEL	Benign	0.15
Sift	Benign	1.0	T;T
Sift4G	Benign	1.0	T;T
Polyphen		0.0010	B;B
Vest4		0.032
ClinPred		0.0033	T
GERP RS		4.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.044
gMVP		0.24

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs2549677; hg19: chr16-2162361; COSMIC: COSV51916816; COSMIC: COSV51916816;