rs2549677

Variant names:

• chr16-2112360-A-G
• rs2549677
• NM_001009944.3:c.3275T>C

Your query was ambiguous. Multiple possible variants found:

• chr16-2112360-A-G
• chr16-2112360-A-C

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 2P and 20B. PM1 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. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in 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:8
• Conservation: PhyloP100: 2.85
• Publications: 17 publications found

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]

PKD1 Gene-Disease associations (from GenCC):

• autosomal dominant polycystic kidney disease

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, ClinGen
• polycystic kidney disease 1

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Laboratory for Molecular Medicine, Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
• autosomal recessive polycystic kidney disease

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• Caroli disease

  Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp

ENSG00000261240 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -18 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 3 benign, 10 uncertain in NM_001009944.3
• 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 Benign/Likely_benign. ClinVar VariationId is 256947.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.457 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001009944.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PKD1	NM_001009944.3	MANE Select	c.3275T>C	p.Met1092Thr	missense	Exon 14 of 46	NP_001009944.3	P98161-1
	PKD1	NM_000296.4		c.3275T>C	p.Met1092Thr	missense	Exon 14 of 46	NP_000287.4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PKD1	ENST00000262304.9	TSL:1 MANE Select	c.3275T>C	p.Met1092Thr	missense	Exon 14 of 46	ENSP00000262304.4	P98161-1
	PKD1	ENST00000423118.5	TSL:1	c.3275T>C	p.Met1092Thr	missense	Exon 14 of 46	ENSP00000399501.1	P98161-3
	PKD1	ENST00000483024.1	TSL:5	c.155T>C	p.Met52Thr	missense	Exon 2 of 5	ENSP00000456670.1	H3BSE8

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

GnomAD2 exomes AF: 0.0721 AC: 15410 AN: 213684 AF XY: 0.0656

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 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

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.434 AC: 11896 AN: 27384

American (AMR) AF: 0.0757 AC: 3259 AN: 43076

Ashkenazi Jewish (ASJ) AF: 0.125 AC: 3057 AN: 24378

East Asian (EAS) AF: 0.000176 AC: 7 AN: 39670

South Asian (SAS) AF: 0.0259 AC: 2191 AN: 84614

European-Finnish (FIN) AF: 0.0619 AC: 2297 AN: 37124

Middle Eastern (MID) AF: 0.147 AC: 565 AN: 3852

European-Non Finnish (NFE) AF: 0.0705 AC: 73737 AN: 1045430

Other (OTH) AF: 0.0967 AC: 5528 AN: 57152

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

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

African (AFR) AF: 0.462 AC: 19152 AN: 41456

American (AMR) AF: 0.136 AC: 2078 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.159 AC: 552 AN: 3470

East Asian (EAS) AF: 0.000579 AC: 3 AN: 5182

South Asian (SAS) AF: 0.0280 AC: 135 AN: 4828

European-Finnish (FIN) AF: 0.0758 AC: 805 AN: 10618

Middle Eastern (MID) AF: 0.194 AC: 57 AN: 294

European-Non Finnish (NFE) AF: 0.0991 AC: 6741 AN: 67998

Other (OTH) AF: 0.190 AC: 401 AN: 2110

Alfa AF: 0.148 Hom.: 515

Bravo AF: 0.217

ExAC AF: 0.0712 AC: 8153

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	2	not specified (2)
-	-	2	Polycystic kidney disease, adult type (2)
-	-	1	Autosomal dominant polycystic kidney disease (1)
-	-	1	Polycystic kidney disease (1)

Computational scores

Source: dbNSFP v4.9

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
MetaRNN	Benign	0.020	T
MetaSVM	Benign	-0.90	T
MutationAssessor	Benign	-2.7	N
PhyloP100		2.9
PrimateAI	Benign	0.41	T
PROVEAN	Benign	2.5	N
REVEL	Benign	0.15
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.0010	B
Vest4		0.032
ClinPred		0.0033	T
GERP RS		4.4
PromoterAI		-0.011	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.044
gMVP		0.24
Mutation Taster		=96/4	polymorphism (auto)

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

Other links and lift over

dbSNP: rs2549677; hg19: chr16-2162361; COSMIC: COSV51916816; COSMIC: COSV51916816;