2-110148020-G-C

Variant names:

• chr2-110148020-G-C
• rs375907280
• NM_001128178.3:c.1165C>G

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS1

The NM_001128178.3(NPHP1):​c.1165C>G​(p.Arg389Gly) variant causes a missense change. The variant allele was found at a frequency of 0.0000253 in 1,582,472 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R389H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000026 (0 hom.)
• Consequence: NPHP1 NM_001128178.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:1
• Conservation: PhyloP100: 4.43
• Publications: 5 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 -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.022318006).
• BP6: Variant 2-110148020-G-C is Benign according to our data. Variant chr2-110148020-G-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 840796.
• BS1: Variant frequency is greater than expected in population eas. GnomAdExome4 allele frequency = 0.0000259 (37/1430390) while in subpopulation EAS AF = 0.000936 (37/39520). AF 95% confidence interval is 0.000697. There are 0 homozygotes in GnomAdExome4. There are 23 alleles in the male GnomAdExome4 subpopulation. Median coverage is 26. This position passed quality control check.

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.1165C>G	p.Arg389Gly	missense	Exon 13 of 20	NP_001121650.1	O15259-2
	NPHP1	NM_000272.5		c.1333C>G	p.Arg445Gly	missense	Exon 13 of 20	NP_000263.2
	NPHP1	NM_207181.4		c.1330C>G	p.Arg444Gly	missense	Exon 13 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.1165C>G	p.Arg389Gly	missense	Exon 13 of 20	ENSP00000389879.3	O15259-2
	NPHP1	ENST00000316534.8	TSL:1	c.1333C>G	p.Arg445Gly	missense	Exon 13 of 20	ENSP00000313169.4	O15259-4
	NPHP1	ENST00000393272.7	TSL:1	c.1330C>G	p.Arg444Gly	missense	Exon 13 of 20	ENSP00000376953.3	O15259-1

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 152082 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000577

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000518 AC: 13 AN: 250970 AF XY: 0.0000516

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000707

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000259 AC: 37 AN: 1430390 Hom.: 0 Cov.: 26 AF XY: 0.0000322 AC XY: 23 AN XY: 713680

African (AFR) AF: 0.00 AC: 0 AN: 32842

American (AMR) AF: 0.00 AC: 0 AN: 44700

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25954

East Asian (EAS) AF: 0.000936 AC: 37 AN: 39520

South Asian (SAS) AF: 0.00 AC: 0 AN: 85666

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53396

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5720

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1083230

Other (OTH) AF: 0.00 AC: 0 AN: 59362

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 152082 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74270

African (AFR) AF: 0.00 AC: 0 AN: 41430

American (AMR) AF: 0.00 AC: 0 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.000577 AC: 3 AN: 5202

South Asian (SAS) AF: 0.00 AC: 0 AN: 4818

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10568

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68004

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.00 Hom.: 0

ExAC AF: 0.0000330 AC: 4

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	1	Inborn genetic diseases (1)
-	1	-	Joubert syndrome with renal defect;C1855681:Nephronophthisis 1;C4551559:Senior-Loken syndrome 1 (1)
-	1	-	Nephronophthisis (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.038
BayesDel_addAF	Benign	-0.44	T
BayesDel_noAF	Benign	-0.49
CADD	Benign	17
DANN	Benign	0.33
DEOGEN2	Benign	0.074	T
Eigen	Benign	-0.85
Eigen_PC	Benign	-0.51
FATHMM_MKL	Benign	0.15	N
LIST_S2	Benign	0.84	T
M_CAP	Benign	0.011	T
MetaRNN	Benign	0.022	T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	-2.5	N
PhyloP100		4.4
PrimateAI	Benign	0.29	T
PROVEAN	Benign	1.8	N
REVEL	Benign	0.11
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.0010	B
Vest4		0.11
MutPred		0.48		Gain of loop (P = 0.069)
MVP		0.63
MPC		0.10
ClinPred		0.039	T
GERP RS		4.8
Varity_R		0.25
gMVP		0.42
Mutation Taster		=88/12	polymorphism

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: rs375907280; hg19: chr2-110905597;