rs2003782

Variant names:

• chr16-2106446-G-A
• rs2003782
• NM_001009944.3:c.7441C>T

Your query was ambiguous. Multiple possible variants found:

• chr16-2106446-G-A
• chr16-2106446-G-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.7441C>T​(p.Leu2481Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.169 in 1,588,648 control chromosomes in the GnomAD database, including 27,594 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.24 (6287 hom., cov: 33)
  • Exomes 𝑓: 0.16 (21307 hom.)
• Consequence: PKD1 NM_001009944.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -0.199
• Publications: 9 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=-0.85).
• BP6: Variant 16-2106446-G-A is Benign according to our data. Variant chr16-2106446-G-A is described in ClinVar as Benign. ClinVar VariationId is 257001.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.199 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.469 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.7441C>T	p.Leu2481Leu	synonymous	Exon 18 of 46	NP_001009944.3	P98161-1
	PKD1	NM_000296.4		c.7441C>T	p.Leu2481Leu	synonymous	Exon 18 of 46	NP_000287.4
	MIR6511B1	NR_106775.1		n.*223C>T		downstream_gene	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PKD1	ENST00000262304.9	TSL:1 MANE Select	c.7441C>T	p.Leu2481Leu	synonymous	Exon 18 of 46	ENSP00000262304.4	P98161-1
	PKD1	ENST00000423118.5	TSL:1	c.7441C>T	p.Leu2481Leu	synonymous	Exon 18 of 46	ENSP00000399501.1	P98161-3
	PKD1	ENST00000415938.7	TSL:5	n.686C>T		non_coding_transcript_exon	Exon 4 of 17

Frequencies

GnomAD3 genomes AF: 0.244 AC: 37139 AN: 152022 Hom.: 6264 Cov.: 33

Gnomad AFR AF: 0.474

Gnomad AMI AF: 0.134

Gnomad AMR AF: 0.177

Gnomad ASJ AF: 0.237

Gnomad EAS AF: 0.00154

Gnomad SAS AF: 0.0906

Gnomad FIN AF: 0.191

Gnomad MID AF: 0.242

Gnomad NFE AF: 0.159

Gnomad OTH AF: 0.237

GnomAD2 exomes AF: 0.155 AC: 27935 AN: 180552 AF XY: 0.151

Gnomad AFR exome AF: 0.491

Gnomad AMR exome AF: 0.111

Gnomad ASJ exome AF: 0.238

Gnomad EAS exome AF: 0.0000722

Gnomad FIN exome AF: 0.190

Gnomad NFE exome AF: 0.163

Gnomad OTH exome AF: 0.174

GnomAD4 exome AF: 0.161 AC: 231041 AN: 1436508 Hom.: 21307 Cov.: 33 AF XY: 0.158 AC XY: 113016 AN XY: 714054

African (AFR) AF: 0.487 AC: 16091 AN: 33016

American (AMR) AF: 0.117 AC: 5014 AN: 42824

Ashkenazi Jewish (ASJ) AF: 0.240 AC: 6198 AN: 25788

East Asian (EAS) AF: 0.000333 AC: 13 AN: 39024

South Asian (SAS) AF: 0.0923 AC: 7815 AN: 84654

European-Finnish (FIN) AF: 0.182 AC: 7878 AN: 43212

Middle Eastern (MID) AF: 0.233 AC: 958 AN: 4114

European-Non Finnish (NFE) AF: 0.160 AC: 176634 AN: 1104386

Other (OTH) AF: 0.175 AC: 10440 AN: 59490

GnomAD4 genome AF: 0.245 AC: 37205 AN: 152140 Hom.: 6287 Cov.: 33 AF XY: 0.241 AC XY: 17909 AN XY: 74392

African (AFR) AF: 0.475 AC: 19691 AN: 41476

American (AMR) AF: 0.177 AC: 2701 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.237 AC: 824 AN: 3470

East Asian (EAS) AF: 0.00154 AC: 8 AN: 5178

South Asian (SAS) AF: 0.0900 AC: 435 AN: 4832

European-Finnish (FIN) AF: 0.191 AC: 2026 AN: 10606

Middle Eastern (MID) AF: 0.243 AC: 71 AN: 292

European-Non Finnish (NFE) AF: 0.159 AC: 10831 AN: 67970

Other (OTH) AF: 0.235 AC: 496 AN: 2114

Alfa AF: 0.200 Hom.: 808

Bravo AF: 0.255

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	2	not specified (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	-0.85
CADD	Benign	1.2
DANN	Benign	0.63
PhyloP100		-0.20
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs2003782; hg19: chr16-2156447; COSMIC: COSV51919269; COSMIC: COSV51919269;