NM_001009944.3:c.11916C>A

Variant names:

• chr16-2090971-G-T
• rs77634115
• NM_001009944.3:c.11916C>A

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 2P and 5B. PM2 BP4_Strong BP7

The NM_001009944.3(PKD1):​c.11916C>A​(p.Arg3972Arg) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000288 in 1,390,888 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. R3972R) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 0.0000029 (0 hom.)
• Consequence: PKD1 NM_001009944.3 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.650
• 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]

PKD1 Gene-Disease associations (from GenCC):

• autosomal dominant polycystic kidney disease

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
• polycystic kidney disease 1

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Laboratory for Molecular Medicine, Genomics England PanelApp
• 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: Likely_benign. The variant received -3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP7: Synonymous conserved (PhyloP=0.65 with no splicing effect.

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.11916C>A	p.Arg3972Arg	synonymous	Exon 43 of 46	NP_001009944.3	P98161-1
	PKD1	NM_000296.4		c.11913C>A	p.Arg3971Arg	synonymous	Exon 43 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.11916C>A	p.Arg3972Arg	synonymous	Exon 43 of 46	ENSP00000262304.4	P98161-1
	PKD1	ENST00000423118.5	TSL:1	c.11913C>A	p.Arg3971Arg	synonymous	Exon 43 of 46	ENSP00000399501.1	P98161-3
	PKD1	ENST00000561668.5	TSL:3	n.*440C>A		non_coding_transcript_exon	Exon 4 of 4	ENSP00000461391.1	I3L4N0

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome AF: 0.00000288 AC: 4 AN: 1390888 Hom.: 0 Cov.: 34 AF XY: 0.00000436 AC XY: 3 AN XY: 687370

African (AFR) AF: 0.0000625 AC: 2 AN: 31990

American (AMR) AF: 0.00 AC: 0 AN: 36350

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25146

East Asian (EAS) AF: 0.00 AC: 0 AN: 36214

South Asian (SAS) AF: 0.0000124 AC: 1 AN: 80588

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 34198

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5686

European-Non Finnish (NFE) AF: 9.24e-7 AC: 1 AN: 1082594

Other (OTH) AF: 0.00 AC: 0 AN: 58122

GnomAD4 genome Cov.: 34

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	5.2
DANN	Benign	0.75
PhyloP100		0.65
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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: rs77634115; hg19: chr16-2140972;