NM_001009944.3:c.3228G>A

Variant names:

• chr16-2112407-C-T
• rs2575316
• NM_001009944.3:c.3228G>A

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 0P and 1B. BP6

The NM_001009944.3(PKD1):​c.3228G>A​(p.Pro1076Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000431 in 1,586,692 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00044 (1 hom., cov: 33)
  • Exomes 𝑓: 0.00043 (0 hom.)
• Consequence: PKD1 NM_001009944.3 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:3
• Conservation: PhyloP100: -0.431
• Publications: 2 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: Likely_benign. The variant received -1 ACMG points.

• BP6: Variant 16-2112407-C-T is Benign according to our data. Variant chr16-2112407-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 256946.

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.3228G>A	p.Pro1076Pro	synonymous	Exon 14 of 46	NP_001009944.3	P98161-1
	PKD1	NM_000296.4		c.3228G>A	p.Pro1076Pro	synonymous	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.3228G>A	p.Pro1076Pro	synonymous	Exon 14 of 46	ENSP00000262304.4	P98161-1
	PKD1	ENST00000423118.5	TSL:1	c.3228G>A	p.Pro1076Pro	synonymous	Exon 14 of 46	ENSP00000399501.1	P98161-3
	PKD1	ENST00000483024.1	TSL:5	c.108G>A	p.Pro36Pro	synonymous	Exon 2 of 5	ENSP00000456670.1	H3BSE8

Frequencies

GnomAD3 genomes AF: 0.000440 AC: 67 AN: 152198 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.0000965

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000523

Gnomad ASJ AF: 0.00173

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000720

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000353 AC: 73 AN: 206672 AF XY: 0.000342

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000249

Gnomad ASJ exome AF: 0.00131

Gnomad EAS exome AF: 0.0000588

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000525

Gnomad OTH exome AF: 0.000374

GnomAD4 exome AF: 0.000430 AC: 617 AN: 1434376 Hom.: 0 Cov.: 32 AF XY: 0.000433 AC XY: 309 AN XY: 713728

African (AFR) AF: 0.0000308 AC: 1 AN: 32512

American (AMR) AF: 0.000249 AC: 11 AN: 44158

Ashkenazi Jewish (ASJ) AF: 0.00170 AC: 44 AN: 25896

East Asian (EAS) AF: 0.00 AC: 0 AN: 39624

South Asian (SAS) AF: 0.00 AC: 0 AN: 85322

European-Finnish (FIN) AF: 0.0000266 AC: 1 AN: 37592

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4120

European-Non Finnish (NFE) AF: 0.000487 AC: 538 AN: 1105436

Other (OTH) AF: 0.000368 AC: 22 AN: 59716

GnomAD4 genome AF: 0.000440 AC: 67 AN: 152316 Hom.: 1 Cov.: 33 AF XY: 0.000470 AC XY: 35 AN XY: 74482

African (AFR) AF: 0.0000962 AC: 4 AN: 41564

American (AMR) AF: 0.000523 AC: 8 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.00173 AC: 6 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000720 AC: 49 AN: 68024

Other (OTH) AF: 0.00 AC: 0 AN: 2112

Alfa AF: 0.000682 Hom.: 1

Bravo AF: 0.000400

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.66
CADD	Benign	15
DANN	Benign	0.65
PhyloP100		-0.43
PromoterAI		-0.0046	Neutral
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.27		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.27		Position offset: -2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs2575316; hg19: chr16-2162408; COSMIC: COSV99237649; COSMIC: COSV99237649;