NM_001009944.3:c.2109C>T

Variant names:

• chr16-2114914-G-A
• rs527655141
• NM_001009944.3:c.2109C>T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_001009944.3(PKD1):​c.2109C>T​(p.His703His) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000846 in 1,530,236 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00096 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00083 (0 hom.)
• Consequence: PKD1 NM_001009944.3 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -3.63

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]

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).
• BP6: Variant 16-2114914-G-A is Benign according to our data. Variant chr16-2114914-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 487359.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2114914-G-A is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=-3.63 with no splicing effect.
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.000965 (147/152352) while in subpopulation AMR AF= 0.00438 (67/15310). AF 95% confidence interval is 0.00354. There are 0 homozygotes in gnomad4. There are 79 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 147 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PKD1	NM_001009944.3	c.2109C>T	p.His703His	synonymous_variant	Exon 11 of 46	ENST00000262304.9	NP_001009944.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PKD1	ENST00000262304.9	c.2109C>T	p.His703His	synonymous_variant	Exon 11 of 46	1	NM_001009944.3	ENSP00000262304.4

Frequencies

GnomAD3 genomes AF: 0.000959 AC: 146 AN: 152234 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00438

Gnomad ASJ AF: 0.00115

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00103

Gnomad OTH AF: 0.000956

GnomAD3 exomes AF: 0.000721 AC: 77 AN: 106850 Hom.: 0 AF XY: 0.000643 AC XY: 36 AN XY: 55962

Gnomad AFR exome AF: 0.000160

Gnomad AMR exome AF: 0.00121

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000682

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00109

Gnomad OTH exome AF: 0.000872

GnomAD4 exome AF: 0.000832 AC: 1147 AN: 1377884 Hom.: 0 Cov.: 30 AF XY: 0.000786 AC XY: 535 AN XY: 680700

Gnomad4 AFR exome AF: 0.0000634

Gnomad4 AMR exome AF: 0.00102

Gnomad4 ASJ exome AF: 0.000556

Gnomad4 EAS exome AF: 0.0000278

Gnomad4 SAS exome AF: 0.000227

Gnomad4 FIN exome AF: 0.0000588

Gnomad4 NFE exome AF: 0.000954

Gnomad4 OTH exome AF: 0.000764

GnomAD4 genome AF: 0.000965 AC: 147 AN: 152352 Hom.: 0 Cov.: 32 AF XY: 0.00106 AC XY: 79 AN XY: 74498

Gnomad4 AFR AF: 0.0000240

Gnomad4 AMR AF: 0.00438

Gnomad4 ASJ AF: 0.00115

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00104

Gnomad4 OTH AF: 0.000946

Alfa AF: 0.00119 Hom.: 2

Bravo AF: 0.000937

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

-

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Feb 09, 2021

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 11967008) -

-

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Polycystic kidney disease, adult type Benign:2

Oct 05, 2021

Fulgent Genetics, Fulgent Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jun 09, 2017

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Polycystic kidney disease Benign:1

-

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

The PKD1 p.His703= variant was not identified in the literature, nor was it identified in the Clinvitae, ClinVar, GeneInsight COGR, MutDB, ADPKD Mutation, PKD1-LOVD, PKD1-LOVD 3.0 databases, or the NHLBI GO Exome Sequencing Project. The variant was identified in dbSNP (ID: rs527655141) as “NA”: in the 1000 Genomes Project in 1 of 5000 chromosomes (frequency: 0.0002): the Exome Aggregation Consortium database (August 8th 2016) in 1 of 2636 chromosomes (freq. 0004) of the European (Non-Finnish) population but not seen in the African, East Asian, European (Finnish), Latino, and South Asian populations; the genome Aggregation Database (beta, October 19th 2016) in 102 (1 homozygous) of 132868 chromosomes (freq.0.0008). However we cannot be certain that data from control databases is specific to PKD1 and not from one of the six PKD1 pseudogenes. The p.His703= variant is not expected to have clinical significance because it does not result in a change of amino acid and is not located in a known consensus splice site. In addition, in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. The variant was identified by our laboratory in a patient with ADPKD with a co-occurring pathogenic PKD1 variant (c.9240_9241del, p.Ala3082CysfsX96), increasing the likelihood that the p.His703= variant does not have clinical significance. In summary, based on the above information, the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	0.13
DANN	Benign	0.71

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

Publications

LitVar

Other links and lift over

dbSNP: rs527655141; hg19: chr16-2164915;