1-179559782-G-C

Variant names:

• chr1-179559782-G-C
• rs12401708
• NM_014625.4:c.452-21C>G

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_014625.4(NPHS2):​c.452-21C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000125 in 1,355,526 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000013 (0 hom.)
• Consequence: NPHS2 NM_014625.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0840
• 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]

NPHS2 Gene-Disease associations (from GenCC):

• nephrotic syndrome, type 2

  Inheritance: AR, AD Classification: DEFINITIVE, STRONG, LIMITED Submitted by: Illumina, Labcorp Genetics (formerly Invitae), Myriad Women’s Health, Ambry Genetics, G2P
• familial idiopathic steroid-resistant nephrotic syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_benign. The variant received -4 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).

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.452-21C>G		intron	N/A	NP_055440.1	Q9NP85-1
	NPHS2	NM_001297575.2		c.452-21C>G		intron	N/A	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.452-21C>G		intron	N/A	ENSP00000356587.4	Q9NP85-1
	NPHS2	ENST00000367616.4	TSL:1	c.452-21C>G		intron	N/A	ENSP00000356588.4	Q9NP85-2
	NPHS2	ENST00000902256.1		c.275-21C>G		intron	N/A	ENSP00000572315.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.0000125 AC: 17 AN: 1355526 Hom.: 0 Cov.: 22 AF XY: 0.00000595 AC XY: 4 AN XY: 672678

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0000980 AC: 3 AN: 30620

American (AMR) AF: 0.00 AC: 0 AN: 38350

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24964

East Asian (EAS) AF: 0.00 AC: 0 AN: 36466

South Asian (SAS) AF: 0.00 AC: 0 AN: 79018

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49844

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5598

European-Non Finnish (NFE) AF: 0.0000135 AC: 14 AN: 1034196

Other (OTH) AF: 0.00 AC: 0 AN: 56470

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	10
DANN	Benign	0.36
PhyloP100		0.084

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.13		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: rs12401708; hg19: chr1-179528917;