rs11675767

chr2-110165126-C-Gchr2-110165126-C-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001128178.3(NPHP1):c.654G>C(p.Glu218Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. E218E) has been classified as Benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: NPHP1 NM_001128178.3 missense
• Clinical Significance: Not reported in ClinVar
• 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]

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.0475412).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NPHP1	NM_001128178.3	c.654G>C	p.Glu218Asp	missense_variant	7/20	ENST00000445609.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NPHP1	ENST00000445609.7	c.654G>C	p.Glu218Asp	missense_variant	7/20	1	NM_001128178.3	P2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.096
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Benign	-0.49
Cadd	Benign	0.14
Dann	Benign	0.93
Eigen	Benign	-1.8
Eigen_PC	Benign	-1.8
FATHMM_MKL	Benign	0.014	N
LIST_S2	Benign	0.57	T;T;T;T;T
M_CAP	Benign	0.022	T
MetaRNN	Benign	0.048	T;T;T;T;T
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	1.1	L;L;L;.;.
MutationTaster	Benign	1.0	P;P;P;P;P
PrimateAI	Benign	0.36	T
PROVEAN	Benign	-0.38	N;N;N;N;N
REVEL	Benign	0.041
Sift	Benign	0.16	T;T;T;T;T
Sift4G	Benign	0.24	T;T;T;T;T
Polyphen		0.054	B;B;B;B;B
Vest4		0.061
MutPred		0.31		Loss of glycosylation at S220 (P = 0.1503);Loss of glycosylation at S220 (P = 0.1503);Loss of glycosylation at S220 (P = 0.1503);.;Loss of glycosylation at S220 (P = 0.1503);
MVP		0.56
MPC		0.075
ClinPred		0.31	T
GERP RS		-6.8
Varity_R		0.039
gMVP		0.16

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;