1-179557080-G-C

Variant names:

• chr1-179557080-G-C
• NM_014625.4:c.685C>G

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1 PM2 PM5 PP3_Moderate

The NM_014625.4(NPHS2):​c.685C>G​(p.Arg229Gly) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,708 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R229Q) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: NPHS2 NM_014625.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.79

Genes affected

NPHS2 (HGNC:13394): (NPHS2 stomatin family member, podocin) This gene encodes a protein that plays a role in the regulation of glomerular permeability. Mutations in this gene cause steroid-resistant nephrotic syndrome. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jul 2014]

ACMG classification

Verdict is Likely_pathogenic. Variant got 8 ACMG points.

• PM1: In a topological_domain Cytoplasmic (size 259) in uniprot entity PODO_HUMAN there are 133 pathogenic changes around while only 3 benign (98%) in NM_014625.4
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr1-179557079-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 5370.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=5, Benign=1, Uncertain_significance=9, Pathogenic=4}.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.918

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NPHS2	NM_014625.4	c.685C>G	p.Arg229Gly	missense_variant	Exon 5 of 8	ENST00000367615.9	NP_055440.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NPHS2	ENST00000367615.9	c.685C>G	p.Arg229Gly	missense_variant	Exon 5 of 8	1	NM_014625.4	ENSP00000356587.4
NPHS2	ENST00000367616.4	c.535-2549C>G		intron_variant	Intron 4 of 6	1		ENSP00000356588.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461708 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 727134

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.36
BayesDel_addAF	Pathogenic	0.41	D
BayesDel_noAF	Pathogenic	0.35
CADD	Uncertain	25
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.94	D
Eigen	Pathogenic	0.69
Eigen_PC	Pathogenic	0.72
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.88	D
M_CAP	Pathogenic	0.33	D
MetaRNN	Pathogenic	0.92	D
MetaSVM	Pathogenic	0.87	D
MutationAssessor	Benign	1.6	L
PrimateAI	Benign	0.42	T
PROVEAN	Pathogenic	-5.1	D
REVEL	Pathogenic	0.84
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.015	D
Polyphen		0.99	D
Vest4		0.73
MutPred		0.73		Gain of catalytic residue at R229 (P = 0.0457);
MVP		0.92
MPC		1.0
ClinPred		1.0	D
GERP RS		5.9
Varity_R		0.91
gMVP		0.79

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr1-179526215;