rs372745980

Variant names:

• chr16-2106953-C-T
• rs372745980
• NM_001009944.3:c.7066-5G>A

Your query was ambiguous. Multiple possible variants found:

• chr16-2106953-C-T
• chr16-2106953-C-A
• chr16-2106953-C-G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001009944.3(PKD1):​c.7066-5G>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00107 in 1,584,788 control chromosomes in the GnomAD database, including 20 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0067 (13 hom., cov: 32)
  • Exomes 𝑓: 0.00047 (7 hom.)
• Consequence: PKD1 NM_001009944.3 splice_region, intron
• Scores: Splicing: ADA: 0.0004365
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.738
• Publications: 0 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP6: Variant 16-2106953-C-T is Benign according to our data. Variant chr16-2106953-C-T is described in ClinVar as Benign. ClinVar VariationId is 256995.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00667 (1013/151830) while in subpopulation AFR AF = 0.0231 (950/41102). AF 95% confidence interval is 0.0219. There are 13 homozygotes in GnomAd4. There are 507 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 13 AD,AR gene

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.7066-5G>A		splice_region intron	N/A	NP_001009944.3	P98161-1
	PKD1	NM_000296.4		c.7066-5G>A		splice_region intron	N/A	NP_000287.4
	MIR6511B1	NR_106775.1		n.-200G>A		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.7066-5G>A		splice_region intron	N/A	ENSP00000262304.4	P98161-1
	PKD1	ENST00000423118.5	TSL:1	c.7066-5G>A		splice_region intron	N/A	ENSP00000399501.1	P98161-3
	PKD1	ENST00000488185.2	TSL:5	c.728-5G>A		splice_region intron	N/A	ENSP00000456672.1	H3BSE9

Frequencies

GnomAD3 genomes AF: 0.00668 AC: 1013 AN: 151716 Hom.: 13 Cov.: 32

Gnomad AFR AF: 0.0232

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00282

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000770

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.00526

GnomAD2 exomes AF: 0.00120 AC: 274 AN: 227430 AF XY: 0.000927

Gnomad AFR exome AF: 0.0165

Gnomad AMR exome AF: 0.000998

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000281

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000472

Gnomad OTH exome AF: 0.00104

GnomAD4 exome AF: 0.000473 AC: 678 AN: 1432958 Hom.: 7 Cov.: 29 AF XY: 0.000413 AC XY: 295 AN XY: 714022

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

African (AFR) AF: 0.0155 AC: 490 AN: 31678

American (AMR) AF: 0.00105 AC: 47 AN: 44640

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26054

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39650

South Asian (SAS) AF: 0.000361 AC: 31 AN: 85990

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 37796

Middle Eastern (MID) AF: 0.00121 AC: 5 AN: 4118

European-Non Finnish (NFE) AF: 0.0000363 AC: 40 AN: 1103336

Other (OTH) AF: 0.00106 AC: 63 AN: 59696

⚠️ 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: 0.00667 AC: 1013 AN: 151830 Hom.: 13 Cov.: 32 AF XY: 0.00683 AC XY: 507 AN XY: 74248

African (AFR) AF: 0.0231 AC: 950 AN: 41102

American (AMR) AF: 0.00281 AC: 43 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.000579 AC: 3 AN: 5180

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10616

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.0000588 AC: 4 AN: 68026

Other (OTH) AF: 0.00521 AC: 11 AN: 2112

Alfa AF: 0.000218 Hom.: 0

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)
-	-	1	not specified (1)
-	-	1	PKD1-related disorder (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	-0.84
CADD	Benign	2.2
DANN	Benign	0.47
PhyloP100		-0.74
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00044
dbscSNV1_RF	Benign	0.066
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: rs372745980; hg19: chr16-2156954;