2-110165126-C-T

Position:

• chr2-110165126-C-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001128178.3(NPHP1):​c.654G>A​(p.Glu218Glu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.351 in 1,610,892 control chromosomes in the GnomAD database, including 104,488 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.39 (12033 hom., cov: 32)
  • Exomes 𝑓: 0.35 (92455 hom.)
• Consequence: NPHP1 NM_001128178.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:16
• Conservation: PhyloP100: -1.68

Genes affected

NPHP1 (HGNC:7905): (nephrocystin 1) This gene encodes a protein with src homology domain 3 (SH3) patterns. This protein interacts with Crk-associated substrate, and it appears to function in the control of cell division, as well as in cell-cell and cell-matrix adhesion signaling, likely as part of a multifunctional complex localized in actin- and microtubule-based structures. Mutations in this gene cause familial juvenile nephronophthisis type 1, a kidney disorder involving both tubules and glomeruli. Defects in this gene are also associated with Senior-Loken syndrome type 1, also referred to as juvenile nephronophthisis with Leber amaurosis, which is characterized by kidney and eye disease, and with Joubert syndrome type 4, which is characterized by cerebellar ataxia, oculomotor apraxia, psychomotor delay and neonatal breathing abnormalities, sometimes including retinal dystrophy and renal disease. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

NPHP1 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP6: Variant 2-110165126-C-T is Benign according to our data. Variant chr2-110165126-C-T is described in ClinVar as [Benign]. Clinvar id is 92719.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-110165126-C-T is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-1.68 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.558 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NPHP1	NM_001128178.3	c.654G>A	p.Glu218Glu	synonymous_variant	7/20	ENST00000445609.7	NP_001121650.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NPHP1	ENST00000445609.7	c.654G>A	p.Glu218Glu	synonymous_variant	7/20	1	NM_001128178.3	ENSP00000389879.3

Frequencies

GnomAD3 genomes AF: 0.385 AC: 58504 AN: 151846 Hom.: 11998 Cov.: 32

Gnomad AFR AF: 0.489

Gnomad AMI AF: 0.347

Gnomad AMR AF: 0.405

Gnomad ASJ AF: 0.332

Gnomad EAS AF: 0.575

Gnomad SAS AF: 0.498

Gnomad FIN AF: 0.225

Gnomad MID AF: 0.404

Gnomad NFE AF: 0.323

Gnomad OTH AF: 0.381

GnomAD3 exomes AF: 0.375 AC: 94183 AN: 251334 Hom.: 19048 AF XY: 0.378 AC XY: 51337 AN XY: 135840

Gnomad AFR exome AF: 0.493

Gnomad AMR exome AF: 0.362

Gnomad ASJ exome AF: 0.329

Gnomad EAS exome AF: 0.594

Gnomad SAS exome AF: 0.501

Gnomad FIN exome AF: 0.226

Gnomad NFE exome AF: 0.326

Gnomad OTH exome AF: 0.352

GnomAD4 exome AF: 0.347 AC: 506143 AN: 1458928 Hom.: 92455 Cov.: 34 AF XY: 0.351 AC XY: 254713 AN XY: 725924

Gnomad4 AFR exome AF: 0.495

Gnomad4 AMR exome AF: 0.365

Gnomad4 ASJ exome AF: 0.331

Gnomad4 EAS exome AF: 0.590

Gnomad4 SAS exome AF: 0.498

Gnomad4 FIN exome AF: 0.230

Gnomad4 NFE exome AF: 0.326

Gnomad4 OTH exome AF: 0.361

GnomAD4 genome AF: 0.386 AC: 58601 AN: 151964 Hom.: 12033 Cov.: 32 AF XY: 0.387 AC XY: 28759 AN XY: 74276

Gnomad4 AFR AF: 0.490

Gnomad4 AMR AF: 0.406

Gnomad4 ASJ AF: 0.332

Gnomad4 EAS AF: 0.575

Gnomad4 SAS AF: 0.499

Gnomad4 FIN AF: 0.225

Gnomad4 NFE AF: 0.323

Gnomad4 OTH AF: 0.380

Alfa AF: 0.342 Hom.: 18262

Bravo AF: 0.399

Asia WGS AF: 0.516 AC: 1791 AN: 3478

EpiCase AF: 0.337

EpiControl AF: 0.336

ClinVar

Significance: Benign

Submissions summary: Benign:16

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:8

Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Mar 23, 2016	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 08, 2016	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Likely benign, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	-	Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -

Senior-Loken syndrome 1 Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Sep 05, 2021	- -

Nephronophthisis 1 Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Sep 05, 2021	- -

Joubert syndrome with renal defect Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Sep 05, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Nephronophthisis Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

not provided Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	0.31
DANN	Benign	0.36

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

Publications

LitVar

Other links and lift over

dbSNP: rs11675767; hg19: chr2-110922703; COSMIC: COSV57208916;