1-179551289-G-C

Variant names:

• chr1-179551289-G-C
• rs1673228202
• NM_014625.4:c.1036C>G
• NPHS2 p.Leu346Val

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 3P and 2B. PM2 PP2 BP4_Moderate

The NM_014625.4(NPHS2):​c.1036C>G​(p.Leu346Val) 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. 13/22 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. L346L) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: NPHS2 NM_014625.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.247
• Publications: 0 publications found

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]

AXDND1 (HGNC:26564): (axonemal dynein light chain domain containing 1)

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 29 curated pathogenic missense variants (we use a threshold of 10). The gene has 4 curated benign missense variants. Gene score misZ: 0.68612 (below the threshold of 3.09). Trascript score misZ: 0.038296 (below the threshold of 3.09). GenCC associations: The gene is linked to familial idiopathic steroid-resistant nephrotic syndrome, nephrotic syndrome, type 2.
• BP4: Computational evidence support a benign effect (MetaRNN=0.11219725).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_014625.4. 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
	NPHS2	NM_014625.4	MANE Select	c.1036C>G	p.Leu346Val	missense	Exon 8 of 8	NP_055440.1	Q9NP85-1
	AXDND1	NM_144696.6	MANE Select	c.3032-3223G>C		intron	N/A	NP_653297.3
	NPHS2	NM_001297575.2		c.832C>G	p.Leu278Val	missense	Exon 7 of 7	NP_001284504.1	Q9NP85-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NPHS2	ENST00000367615.9	TSL:1 MANE Select	c.1036C>G	p.Leu346Val	missense	Exon 8 of 8	ENSP00000356587.4	Q9NP85-1
	NPHS2	ENST00000367616.4	TSL:1	c.832C>G	p.Leu278Val	missense	Exon 7 of 7	ENSP00000356588.4	Q9NP85-2
	AXDND1	ENST00000367618.8	TSL:1 MANE Select	c.3032-3223G>C		intron	N/A	ENSP00000356590.3	Q5T1B0-1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 41

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000936 Hom.: 0

Bravo AF: 0.00000756

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.077
BayesDel_addAF	Benign	-0.0046	T
BayesDel_noAF	Benign	-0.24
CADD	Benign	5.8
DANN	Benign	0.92
DEOGEN2	Benign	0.35	T
Eigen	Benign	-1.0
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.099	N
LIST_S2	Benign	0.46	T
M_CAP	Uncertain	0.12	D
MetaRNN	Benign	0.11	T
MetaSVM	Uncertain	0.70	D
MutationAssessor	Uncertain	2.2	M
PhyloP100		-0.25
PrimateAI	Benign	0.32	T
PROVEAN	Benign	-1.3	N
REVEL	Uncertain	0.33
Sift	Benign	0.32	T
Sift4G	Benign	0.23	T
Varity_R		0.039
gMVP		0.47
Mutation Taster		=86/14	polymorphism

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs1673228202;

hg19: chr1-179520424;