rs11675767

Variant names:

• chr2-110165126-C-T
• rs11675767
• NM_001128178.3:c.654G>A

Your query was ambiguous. Multiple possible variants found:

• chr2-110165126-C-T
• chr2-110165126-C-G

Variant summary

Our verdict is Benign. The variant received -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:17
• Conservation: PhyloP100: -1.68
• Publications: 27 publications found

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 Gene-Disease associations (from GenCC):

• Joubert syndrome with renal defect

  Inheritance: AR Classification: DEFINITIVE, MODERATE, SUPPORTIVE Submitted by: Orphanet, Ambry Genetics, G2P
• nephronophthisis 1

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: ClinGen, Orphanet, Labcorp Genetics (formerly Invitae), G2P
• Bardet-Biedl syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• Senior-Loken syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -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 VariationId is 92719.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001128178.3. 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
	NPHP1	NM_001128178.3	MANE Select	c.654G>A	p.Glu218Glu	synonymous	Exon 7 of 20	NP_001121650.1	O15259-2
	NPHP1	NM_000272.5		c.654G>A	p.Glu218Glu	synonymous	Exon 7 of 20	NP_000263.2
	NPHP1	NM_207181.4		c.654G>A	p.Glu218Glu	synonymous	Exon 7 of 20	NP_997064.2	O15259-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NPHP1	ENST00000445609.7	TSL:1 MANE Select	c.654G>A	p.Glu218Glu	synonymous	Exon 7 of 20	ENSP00000389879.3	O15259-2
	NPHP1	ENST00000316534.8	TSL:1	c.654G>A	p.Glu218Glu	synonymous	Exon 7 of 20	ENSP00000313169.4	O15259-4
	NPHP1	ENST00000393272.7	TSL:1	c.654G>A	p.Glu218Glu	synonymous	Exon 7 of 20	ENSP00000376953.3	O15259-1

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

GnomAD2 exomes AF: 0.375 AC: 94183 AN: 251334 AF XY: 0.378

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 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

African (AFR) AF: 0.495 AC: 16516 AN: 33366

American (AMR) AF: 0.365 AC: 16318 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.331 AC: 8639 AN: 26106

East Asian (EAS) AF: 0.590 AC: 23392 AN: 39638

South Asian (SAS) AF: 0.498 AC: 42865 AN: 86160

European-Finnish (FIN) AF: 0.230 AC: 12276 AN: 53386

Middle Eastern (MID) AF: 0.393 AC: 2263 AN: 5760

European-Non Finnish (NFE) AF: 0.326 AC: 362138 AN: 1109534

Other (OTH) AF: 0.361 AC: 21736 AN: 60258

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

African (AFR) AF: 0.490 AC: 20289 AN: 41426

American (AMR) AF: 0.406 AC: 6193 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.332 AC: 1152 AN: 3468

East Asian (EAS) AF: 0.575 AC: 2966 AN: 5156

South Asian (SAS) AF: 0.499 AC: 2404 AN: 4814

European-Finnish (FIN) AF: 0.225 AC: 2378 AN: 10556

Middle Eastern (MID) AF: 0.411 AC: 120 AN: 292

European-Non Finnish (NFE) AF: 0.323 AC: 21983 AN: 67970

Other (OTH) AF: 0.380 AC: 801 AN: 2106

Alfa AF: 0.351 Hom.: 29590

Bravo AF: 0.399

Asia WGS AF: 0.516 AC: 1791 AN: 3478

EpiCase AF: 0.337

EpiControl AF: 0.336

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	9	not specified (9)
-	-	2	Joubert syndrome with renal defect (2)
-	-	2	Nephronophthisis 1 (2)
-	-	2	Senior-Loken syndrome 1 (2)
-	-	1	Nephronophthisis (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	0.31
DANN	Benign	0.36
PhyloP100		-1.7
Mutation Taster		=100/0	polymorphism (auto)

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