rs2457533

Variant names:

• chr16-2106849-A-G
• rs2457533
• NM_001009944.3:c.7165T>C

Your query was ambiguous. Multiple possible variants found:

• chr16-2106849-A-G
• chr16-2106849-A-T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001009944.3(PKD1):​c.7165T>C​(p.Leu2389Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.113 in 1,378,590 control chromosomes in the GnomAD database, including 18,957 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.27 (7297 hom., cov: 30)
  • Exomes 𝑓: 0.094 (11660 hom.)
• Consequence: PKD1 NM_001009944.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 3.26
• Publications: 11 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]

MIR6511B1 (HGNC:50228): (microRNA 6511b-1) microRNAs (miRNAs) are short (20-24 nt) non-coding RNAs that are involved in post-transcriptional regulation of gene expression in multicellular organisms by affecting both the stability and translation of mRNAs. miRNAs are transcribed by RNA polymerase II as part of capped and polyadenylated primary transcripts (pri-miRNAs) that can be either protein-coding or non-coding. The primary transcript is cleaved by the Drosha ribonuclease III enzyme to produce an approximately 70-nt stem-loop precursor miRNA (pre-miRNA), which is further cleaved by the cytoplasmic Dicer ribonuclease to generate the mature miRNA and antisense miRNA star (miRNA*) products. The mature miRNA is incorporated into a RNA-induced silencing complex (RISC), which recognizes target mRNAs through imperfect base pairing with the miRNA and most commonly results in translational inhibition or destabilization of the target mRNA. The RefSeq represents the predicted microRNA stem-loop. [provided by RefSeq, Sep 2009]

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.61).
• BP6: Variant 16-2106849-A-G is Benign according to our data. Variant chr16-2106849-A-G is described in ClinVar as Benign. ClinVar VariationId is 256997.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=3.26 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.506 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.7165T>C	p.Leu2389Leu	synonymous	Exon 17 of 46	NP_001009944.3	P98161-1
	PKD1	NM_000296.4		c.7165T>C	p.Leu2389Leu	synonymous	Exon 17 of 46	NP_000287.4
	MIR6511B1	NR_106775.1		n.-96T>C		upstream_gene	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PKD1	ENST00000262304.9	TSL:1 MANE Select	c.7165T>C	p.Leu2389Leu	synonymous	Exon 17 of 46	ENSP00000262304.4	P98161-1
	PKD1	ENST00000423118.5	TSL:1	c.7165T>C	p.Leu2389Leu	synonymous	Exon 17 of 46	ENSP00000399501.1	P98161-3
	PKD1	ENST00000483024.1	TSL:5	c.331T>C	p.Leu111Leu	synonymous	Exon 4 of 5	ENSP00000456670.1	H3BSE8

Frequencies

GnomAD3 genomes AF: 0.268 AC: 40243 AN: 150008 Hom.: 7270 Cov.: 30

Gnomad AFR AF: 0.511

Gnomad AMI AF: 0.127

Gnomad AMR AF: 0.192

Gnomad ASJ AF: 0.284

Gnomad EAS AF: 0.0317

Gnomad SAS AF: 0.125

Gnomad FIN AF: 0.239

Gnomad MID AF: 0.264

Gnomad NFE AF: 0.176

Gnomad OTH AF: 0.262

GnomAD2 exomes AF: 0.143 AC: 27649 AN: 192938 AF XY: 0.140

Gnomad AFR exome AF: 0.471

Gnomad AMR exome AF: 0.105

Gnomad ASJ exome AF: 0.248

Gnomad EAS exome AF: 0.0207

Gnomad FIN exome AF: 0.190

Gnomad NFE exome AF: 0.141

Gnomad OTH exome AF: 0.173

GnomAD4 exome AF: 0.0943 AC: 115809 AN: 1228468 Hom.: 11660 Cov.: 30 AF XY: 0.0944 AC XY: 58085 AN XY: 615468

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

African (AFR) AF: 0.397 AC: 8929 AN: 22482

American (AMR) AF: 0.0908 AC: 3787 AN: 41688

Ashkenazi Jewish (ASJ) AF: 0.214 AC: 4764 AN: 22306

East Asian (EAS) AF: 0.0347 AC: 1364 AN: 39334

South Asian (SAS) AF: 0.0891 AC: 7155 AN: 80260

European-Finnish (FIN) AF: 0.205 AC: 7307 AN: 35666

Middle Eastern (MID) AF: 0.186 AC: 651 AN: 3494

European-Non Finnish (NFE) AF: 0.0807 AC: 75125 AN: 930674

Other (OTH) AF: 0.128 AC: 6727 AN: 52564

⚠️ 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: 0.269 AC: 40313 AN: 150122 Hom.: 7297 Cov.: 30 AF XY: 0.265 AC XY: 19432 AN XY: 73274

African (AFR) AF: 0.511 AC: 20562 AN: 40206

American (AMR) AF: 0.191 AC: 2904 AN: 15174

Ashkenazi Jewish (ASJ) AF: 0.284 AC: 977 AN: 3446

East Asian (EAS) AF: 0.0314 AC: 162 AN: 5156

South Asian (SAS) AF: 0.124 AC: 593 AN: 4780

European-Finnish (FIN) AF: 0.239 AC: 2500 AN: 10444

Middle Eastern (MID) AF: 0.271 AC: 79 AN: 292

European-Non Finnish (NFE) AF: 0.176 AC: 11882 AN: 67640

Other (OTH) AF: 0.259 AC: 540 AN: 2084

Alfa AF: 0.227 Hom.: 925

Bravo AF: 0.281

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not specified (3)
-	-	2	not provided (2)
-	-	1	Autosomal dominant polycystic kidney disease (1)
-	-	1	Polycystic kidney disease (1)
-	-	1	Polycystic kidney disease, adult type (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.61
CADD	Benign	7.7
DANN	Benign	0.43
PhyloP100		3.3
Mutation Taster		=100/0	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: rs2457533; hg19: chr16-2156850; COSMIC: COSV51921397; COSMIC: COSV51921397;