rs12401708

Variant names:

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

Your query was ambiguous. Multiple possible variants found:

• chr1-179559782-G-A
• chr1-179559782-G-C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_014625.4(NPHS2):​c.452-21C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.253 in 1,505,300 control chromosomes in the GnomAD database, including 50,838 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.20 (3797 hom., cov: 32)
  • Exomes 𝑓: 0.26 (47041 hom.)
• Consequence: NPHS2 NM_014625.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.0840
• Publications: 8 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BP6: Variant 1-179559782-G-A is Benign according to our data. Variant chr1-179559782-G-A is described in ClinVar as Benign. ClinVar VariationId is 1180466.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.269 is higher than 0.05.

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

Frequencies

GnomAD3 genomes AF: 0.202 AC: 30745 AN: 151988 Hom.: 3794 Cov.: 32

Gnomad AFR AF: 0.0696

Gnomad AMI AF: 0.202

Gnomad AMR AF: 0.203

Gnomad ASJ AF: 0.342

Gnomad EAS AF: 0.0484

Gnomad SAS AF: 0.193

Gnomad FIN AF: 0.307

Gnomad MID AF: 0.225

Gnomad NFE AF: 0.272

Gnomad OTH AF: 0.205

GnomAD2 exomes AF: 0.238 AC: 41420 AN: 174312 AF XY: 0.241

Gnomad AFR exome AF: 0.0633

Gnomad AMR exome AF: 0.241

Gnomad ASJ exome AF: 0.362

Gnomad EAS exome AF: 0.0432

Gnomad FIN exome AF: 0.309

Gnomad NFE exome AF: 0.275

Gnomad OTH exome AF: 0.256

GnomAD4 exome AF: 0.258 AC: 349490 AN: 1353192 Hom.: 47041 Cov.: 22 AF XY: 0.258 AC XY: 173169 AN XY: 671596

African (AFR) AF: 0.0600 AC: 1835 AN: 30600

American (AMR) AF: 0.234 AC: 8983 AN: 38328

Ashkenazi Jewish (ASJ) AF: 0.350 AC: 8735 AN: 24942

East Asian (EAS) AF: 0.0719 AC: 2623 AN: 36456

South Asian (SAS) AF: 0.208 AC: 16394 AN: 78968

European-Finnish (FIN) AF: 0.308 AC: 15345 AN: 49792

Middle Eastern (MID) AF: 0.239 AC: 1336 AN: 5590

European-Non Finnish (NFE) AF: 0.272 AC: 280635 AN: 1032122

Other (OTH) AF: 0.241 AC: 13604 AN: 56394

GnomAD4 genome AF: 0.202 AC: 30761 AN: 152108 Hom.: 3797 Cov.: 32 AF XY: 0.203 AC XY: 15110 AN XY: 74346

African (AFR) AF: 0.0694 AC: 2884 AN: 41532

American (AMR) AF: 0.203 AC: 3110 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.342 AC: 1188 AN: 3470

East Asian (EAS) AF: 0.0483 AC: 250 AN: 5174

South Asian (SAS) AF: 0.194 AC: 937 AN: 4818

European-Finnish (FIN) AF: 0.307 AC: 3240 AN: 10558

Middle Eastern (MID) AF: 0.224 AC: 66 AN: 294

European-Non Finnish (NFE) AF: 0.272 AC: 18475 AN: 67956

Other (OTH) AF: 0.203 AC: 427 AN: 2108

Alfa AF: 0.255 Hom.: 1032

Bravo AF: 0.188

Asia WGS AF: 0.111 AC: 385 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Nephrotic syndrome, type 2 (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	1.7
DANN	Benign	0.53
PhyloP100		0.084
Mutation Taster		=100/0	polymorphism (auto)

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: rs12401708; hg19: chr1-179528917;