1-179550964-G-C

Variant names:

• chr1-179550964-G-C
• rs193266499
• NM_014625.4:c.*209C>G

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_014625.4(NPHS2):​c.*209C>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0018 in 626,764 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0015 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0019 (4 hom.)
• Consequence: NPHS2 NM_014625.4 3_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.0620
• 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: Benign. The variant received -8 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BS2: High Homozygotes in GnomAdExome4 at 4 AR,AD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NPHS2	NM_014625.4	c.*209C>G		3_prime_UTR_variant	Exon 8 of 8	ENST00000367615.9	NP_055440.1
AXDND1	NM_144696.6	c.3032-3548G>C		intron_variant	Intron 25 of 25	ENST00000367618.8	NP_653297.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NPHS2	ENST00000367615.9	c.*209C>G		3_prime_UTR_variant	Exon 8 of 8	1	NM_014625.4	ENSP00000356587.4
AXDND1	ENST00000367618.8	c.3032-3548G>C		intron_variant	Intron 25 of 25	1	NM_144696.6	ENSP00000356590.3

Frequencies

GnomAD3 genomes AF: 0.00152 AC: 232 AN: 152192 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000410

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00141

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00282

Gnomad OTH AF: 0.00191

GnomAD4 exome AF: 0.00189 AC: 895 AN: 474454 Hom.: 4 Cov.: 5 AF XY: 0.00179 AC XY: 450 AN XY: 250972

African (AFR) AF: 0.000907 AC: 12 AN: 13232

American (AMR) AF: 0.000265 AC: 6 AN: 22674

Ashkenazi Jewish (ASJ) AF: 0.000209 AC: 3 AN: 14334

East Asian (EAS) AF: 0.00 AC: 0 AN: 30194

South Asian (SAS) AF: 0.00 AC: 0 AN: 47872

European-Finnish (FIN) AF: 0.00241 AC: 68 AN: 28188

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2028

European-Non Finnish (NFE) AF: 0.00266 AC: 770 AN: 289310

Other (OTH) AF: 0.00135 AC: 36 AN: 26622

GnomAD4 genome AF: 0.00152 AC: 232 AN: 152310 Hom.: 0 Cov.: 33 AF XY: 0.00122 AC XY: 91 AN XY: 74476

African (AFR) AF: 0.000409 AC: 17 AN: 41558

American (AMR) AF: 0.000196 AC: 3 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.000288 AC: 1 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00141 AC: 15 AN: 10614

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00282 AC: 192 AN: 68030

Other (OTH) AF: 0.00189 AC: 4 AN: 2114

Alfa AF: 0.00127 Hom.: 0

Bravo AF: 0.00133

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Nephrotic syndrome, type 2 Uncertain:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	3.6
DANN	Benign	0.53
PhyloP100		-0.062
Mutation Taster		=100/0	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

Other links and lift over

dbSNP: rs193266499; hg19: chr1-179520099;