NM_001009944.3:c.1710C>T

Variant names:

• chr16-2116541-G-A
• rs367983387
• NM_001009944.3:c.1710C>T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_001009944.3(PKD1):​c.1710C>T​(p.His570His) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00638 in 1,540,920 control chromosomes in the GnomAD database, including 44 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0057 (2 hom., cov: 33)
  • Exomes 𝑓: 0.0065 (42 hom.)
• Consequence: PKD1 NM_001009944.3 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -0.710
• Publications: 4 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BP6: Variant 16-2116541-G-A is Benign according to our data. Variant chr16-2116541-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 256926.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.71 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00566 (862/152282) while in subpopulation NFE AF = 0.00776 (528/68006). AF 95% confidence interval is 0.00722. There are 2 homozygotes in GnomAd4. There are 447 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 2 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.1710C>T	p.His570His	synonymous	Exon 8 of 46	NP_001009944.3	P98161-1
	PKD1	NM_000296.4		c.1710C>T	p.His570His	synonymous	Exon 8 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.1710C>T	p.His570His	synonymous	Exon 8 of 46	ENSP00000262304.4	P98161-1
	PKD1	ENST00000423118.5	TSL:1	c.1710C>T	p.His570His	synonymous	Exon 8 of 46	ENSP00000399501.1	P98161-3
	PKD1	ENST00000488185.2	TSL:5	c.470+948C>T		intron	N/A	ENSP00000456672.1	H3BSE9

Frequencies

GnomAD3 genomes AF: 0.00566 AC: 862 AN: 152164 Hom.: 2 Cov.: 33

Gnomad AFR AF: 0.00135

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.000392

Gnomad ASJ AF: 0.00375

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00186

Gnomad FIN AF: 0.0231

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00776

Gnomad OTH AF: 0.00192

GnomAD2 exomes AF: 0.00498 AC: 857 AN: 172122 AF XY: 0.00530

Gnomad AFR exome AF: 0.000841

Gnomad AMR exome AF: 0.000393

Gnomad ASJ exome AF: 0.00320

Gnomad EAS exome AF: 0.0000750

Gnomad FIN exome AF: 0.0208

Gnomad NFE exome AF: 0.00691

Gnomad OTH exome AF: 0.00296

GnomAD4 exome AF: 0.00646 AC: 8976 AN: 1388638 Hom.: 42 Cov.: 30 AF XY: 0.00644 AC XY: 4436 AN XY: 688646

African (AFR) AF: 0.000880 AC: 28 AN: 31804

American (AMR) AF: 0.000464 AC: 18 AN: 38832

Ashkenazi Jewish (ASJ) AF: 0.00376 AC: 95 AN: 25284

East Asian (EAS) AF: 0.0000271 AC: 1 AN: 36950

South Asian (SAS) AF: 0.00284 AC: 228 AN: 80356

European-Finnish (FIN) AF: 0.0220 AC: 908 AN: 41360

Middle Eastern (MID) AF: 0.00123 AC: 5 AN: 4054

European-Non Finnish (NFE) AF: 0.00689 AC: 7387 AN: 1072254

Other (OTH) AF: 0.00530 AC: 306 AN: 57744

GnomAD4 genome AF: 0.00566 AC: 862 AN: 152282 Hom.: 2 Cov.: 33 AF XY: 0.00600 AC XY: 447 AN XY: 74452

African (AFR) AF: 0.00135 AC: 56 AN: 41560

American (AMR) AF: 0.000392 AC: 6 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.00375 AC: 13 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5174

South Asian (SAS) AF: 0.00186 AC: 9 AN: 4830

European-Finnish (FIN) AF: 0.0231 AC: 245 AN: 10618

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

European-Non Finnish (NFE) AF: 0.00776 AC: 528 AN: 68006

Other (OTH) AF: 0.00190 AC: 4 AN: 2110

Alfa AF: 0.00556 Hom.: 4

Bravo AF: 0.00382

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	Polycystic kidney disease, adult type (3)
-	-	2	not provided (2)
-	-	1	not specified (1)
-	-	1	PKD1-related disorder (1)
-	-	1	Polycystic kidney disease (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	5.5
DANN	Benign	0.54
PhyloP100		-0.71
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=96/4	polymorphism

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: rs367983387; hg19: chr16-2166542; COSMIC: COSV99237287; COSMIC: COSV99237287;