NM_001009944.3:c.9330T>C

Variant names:

• chr16-2102128-A-G
• rs12926160
• NM_001009944.3:c.9330T>C

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 0P and 17B. BP4_Strong BP6_Very_Strong BP7 BS2

The NM_001009944.3(PKD1):​c.9330T>C​(p.Pro3110Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0677 in 1,536,054 control chromosomes in the GnomAD database, including 13,168 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.23 (5904 hom., cov: 31)
  • Exomes 𝑓: 0.050 (7264 hom.)
• Consequence: PKD1 NM_001009944.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -2.67
• Publications: 6 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

ACMG classification

Our verdict: Benign. The variant received -17 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-1.01).
• BP6: Variant 16-2102128-A-G is Benign according to our data. Variant chr16-2102128-A-G is described in ClinVar as Benign. ClinVar VariationId is 257042.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-2.67 with no splicing effect.
• BS2: High Homozygotes in GnomAd4 at 5904 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.9330T>C	p.Pro3110Pro	synonymous	Exon 26 of 46	NP_001009944.3	P98161-1
	PKD1	NM_000296.4		c.9330T>C	p.Pro3110Pro	synonymous	Exon 26 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.9330T>C	p.Pro3110Pro	synonymous	Exon 26 of 46	ENSP00000262304.4	P98161-1
	PKD1	ENST00000423118.5	TSL:1	c.9330T>C	p.Pro3110Pro	synonymous	Exon 26 of 46	ENSP00000399501.1	P98161-3
	PKD1	ENST00000480227.5	TSL:1	n.1067T>C		non_coding_transcript_exon	Exon 4 of 8

Frequencies

GnomAD3 genomes AF: 0.235 AC: 34200 AN: 145742 Hom.: 5893 Cov.: 31

Gnomad AFR AF: 0.481

Gnomad AMI AF: 0.0865

Gnomad AMR AF: 0.170

Gnomad ASJ AF: 0.221

Gnomad EAS AF: 0.00154

Gnomad SAS AF: 0.0612

Gnomad FIN AF: 0.168

Gnomad MID AF: 0.232

Gnomad NFE AF: 0.152

Gnomad OTH AF: 0.226

GnomAD2 exomes AF: 0.0326 AC: 7348 AN: 225576 AF XY: 0.0291

Gnomad AFR exome AF: 0.250

Gnomad AMR exome AF: 0.0274

Gnomad ASJ exome AF: 0.0374

Gnomad EAS exome AF: 0.0000548

Gnomad FIN exome AF: 0.00557

Gnomad NFE exome AF: 0.0284

Gnomad OTH exome AF: 0.0376

GnomAD4 exome AF: 0.0501 AC: 69691 AN: 1390220 Hom.: 7264 Cov.: 31 AF XY: 0.0509 AC XY: 35249 AN XY: 692220

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

African (AFR) AF: 0.238 AC: 6341 AN: 26590

American (AMR) AF: 0.0637 AC: 2782 AN: 43700

Ashkenazi Jewish (ASJ) AF: 0.130 AC: 3267 AN: 25046

East Asian (EAS) AF: 0.000202 AC: 8 AN: 39668

South Asian (SAS) AF: 0.0402 AC: 3404 AN: 84728

European-Finnish (FIN) AF: 0.111 AC: 5399 AN: 48608

Middle Eastern (MID) AF: 0.115 AC: 454 AN: 3946

European-Non Finnish (NFE) AF: 0.0408 AC: 43225 AN: 1060084

Other (OTH) AF: 0.0832 AC: 4811 AN: 57850

⚠️ 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: 0.235 AC: 34242 AN: 145834 Hom.: 5904 Cov.: 31 AF XY: 0.227 AC XY: 16163 AN XY: 71092

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

African (AFR) AF: 0.481 AC: 18336 AN: 38144

American (AMR) AF: 0.170 AC: 2505 AN: 14772

Ashkenazi Jewish (ASJ) AF: 0.221 AC: 748 AN: 3380

East Asian (EAS) AF: 0.00154 AC: 8 AN: 5182

South Asian (SAS) AF: 0.0612 AC: 290 AN: 4742

European-Finnish (FIN) AF: 0.168 AC: 1701 AN: 10096

Middle Eastern (MID) AF: 0.232 AC: 66 AN: 284

European-Non Finnish (NFE) AF: 0.152 AC: 10053 AN: 66298

Other (OTH) AF: 0.224 AC: 458 AN: 2046

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.315 Hom.: 3897

ClinVar

ClinVar submissions

Significance: 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
BayesDel_noAF	Benign	-1.0
CADD	Benign	0.063
DANN	Benign	0.38
PhyloP100		-2.7
Mutation Taster		=86/14	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs12926160; hg19: chr16-2152129; COSMIC: COSV51913910; COSMIC: COSV51913910;