1-179551119-C-G

Position:

• chr1-179551119-C-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_014625.4(NPHS2):​c.*54G>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.619 in 1,607,334 control chromosomes in the GnomAD database, including 309,162 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.61 (28879 hom., cov: 31)
  • Exomes 𝑓: 0.62 (280283 hom.)
• Consequence: NPHS2 NM_014625.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.952

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)

AXDND1 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant 1-179551119-C-G is Benign according to our data. Variant chr1-179551119-C-G is described in ClinVar as [Benign]. Clinvar id is 293845.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-179551119-C-G is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.628 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NPHS2	NM_014625.4	c.*54G>C		3_prime_UTR_variant	8/8	ENST00000367615.9	NP_055440.1
AXDND1	NM_144696.6	c.3032-3393C>G		intron_variant		ENST00000367618.8	NP_653297.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NPHS2	ENST00000367615	c.*54G>C		3_prime_UTR_variant	8/8	1	NM_014625.4	ENSP00000356587.4
AXDND1	ENST00000367618.8	c.3032-3393C>G		intron_variant		1	NM_144696.6	ENSP00000356590.3

Frequencies

GnomAD3 genomes AF: 0.615 AC: 93387 AN: 151920 Hom.: 28851 Cov.: 31

Gnomad AFR AF: 0.604

Gnomad AMI AF: 0.647

Gnomad AMR AF: 0.638

Gnomad ASJ AF: 0.640

Gnomad EAS AF: 0.468

Gnomad SAS AF: 0.591

Gnomad FIN AF: 0.620

Gnomad MID AF: 0.604

Gnomad NFE AF: 0.626

Gnomad OTH AF: 0.608

GnomAD4 exome AF: 0.620 AC: 901687 AN: 1455296 Hom.: 280283 Cov.: 30 AF XY: 0.620 AC XY: 448858 AN XY: 724316

Gnomad4 AFR exome AF: 0.601

Gnomad4 AMR exome AF: 0.664

Gnomad4 ASJ exome AF: 0.659

Gnomad4 EAS exome AF: 0.507

Gnomad4 SAS exome AF: 0.602

Gnomad4 FIN exome AF: 0.624

Gnomad4 NFE exome AF: 0.622

Gnomad4 OTH exome AF: 0.619

GnomAD4 genome AF: 0.615 AC: 93471 AN: 152038 Hom.: 28879 Cov.: 31 AF XY: 0.613 AC XY: 45580 AN XY: 74302

Gnomad4 AFR AF: 0.604

Gnomad4 AMR AF: 0.639

Gnomad4 ASJ AF: 0.640

Gnomad4 EAS AF: 0.468

Gnomad4 SAS AF: 0.591

Gnomad4 FIN AF: 0.620

Gnomad4 NFE AF: 0.626

Gnomad4 OTH AF: 0.609

Alfa AF: 0.509 Hom.: 1425

Bravo AF: 0.617

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Nephrotic syndrome, type 2 Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 08, 2021	- -

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 12, 2018	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Jul 15, 2024

This variant is classified as Benign based on local population frequency. This variant was detected in 81% of patients studied in a panel designed for Epileptic and Developmental Encephalopathy and Progressive Myoclonus Epilepsy. Number of patients: 75. Only high quality variants are reported. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	4.2
DANN	Benign	0.44

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: rs1410591; hg19: chr1-179520254; COSMIC: COSV62634863; COSMIC: COSV62634863;