1-179575778-G-C

Variant names:

• chr1-179575778-G-C
• rs12123397
• NM_014625.4:c.87C>G

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_Strong BP6 BP7 BS2

The NM_014625.4(NPHS2):​c.87C>G​(p.Ala29Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00557 in 1,497,754 control chromosomes in the GnomAD database, including 35 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. A29A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0043 (0 hom., cov: 34)
  • Exomes 𝑓: 0.0057 (35 hom.)
• Consequence: NPHS2 NM_014625.4 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:7
• Conservation: PhyloP100: -1.24
• Publications: 2 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: Myriad Women’s Health, Ambry Genetics, Labcorp Genetics (formerly Invitae), Illumina, G2P
• familial idiopathic steroid-resistant nephrotic syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BP6: Variant 1-179575778-G-C is Benign according to our data. Variant chr1-179575778-G-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 260431.
• BP7: Synonymous conserved (PhyloP=-1.24 with no splicing effect.
• BS2: High Homozygotes in GnomAdExome4 at 35 AR,AD gene

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.87C>G	p.Ala29Ala	synonymous	Exon 1 of 8	NP_055440.1
	NPHS2	NM_001297575.2		c.87C>G	p.Ala29Ala	synonymous	Exon 1 of 7	NP_001284504.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NPHS2	ENST00000367615.9	TSL:1 MANE Select	c.87C>G	p.Ala29Ala	synonymous	Exon 1 of 8	ENSP00000356587.4
	NPHS2	ENST00000367616.4	TSL:1	c.87C>G	p.Ala29Ala	synonymous	Exon 1 of 7	ENSP00000356588.4
	NPHS2	ENST00000902256.1		c.87C>G	p.Ala29Ala	synonymous	Exon 1 of 6	ENSP00000572315.1

Frequencies

GnomAD3 genomes AF: 0.00427 AC: 649 AN: 152076 Hom.: 0 Cov.: 34

Gnomad AFR AF: 0.000941

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00569

Gnomad ASJ AF: 0.00259

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00497

Gnomad FIN AF: 0.00972

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00563

Gnomad OTH AF: 0.00191

GnomAD2 exomes AF: 0.00480 AC: 486 AN: 101244 AF XY: 0.00522

Gnomad AFR exome AF: 0.00121

Gnomad AMR exome AF: 0.00331

Gnomad ASJ exome AF: 0.00192

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00793

Gnomad NFE exome AF: 0.00544

Gnomad OTH exome AF: 0.00369

GnomAD4 exome AF: 0.00572 AC: 7694 AN: 1345570 Hom.: 35 Cov.: 37 AF XY: 0.00583 AC XY: 3872 AN XY: 664110

African (AFR) AF: 0.000543 AC: 15 AN: 27636

American (AMR) AF: 0.00368 AC: 105 AN: 28558

Ashkenazi Jewish (ASJ) AF: 0.00208 AC: 48 AN: 23088

East Asian (EAS) AF: 0.00 AC: 0 AN: 32492

South Asian (SAS) AF: 0.00783 AC: 575 AN: 73416

European-Finnish (FIN) AF: 0.0105 AC: 412 AN: 39198

Middle Eastern (MID) AF: 0.00150 AC: 8 AN: 5330

European-Non Finnish (NFE) AF: 0.00592 AC: 6273 AN: 1060102

Other (OTH) AF: 0.00463 AC: 258 AN: 55750

GnomAD4 genome AF: 0.00426 AC: 649 AN: 152184 Hom.: 0 Cov.: 34 AF XY: 0.00468 AC XY: 348 AN XY: 74382

African (AFR) AF: 0.000939 AC: 39 AN: 41548

American (AMR) AF: 0.00569 AC: 87 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.00259 AC: 9 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5128

South Asian (SAS) AF: 0.00497 AC: 24 AN: 4828

European-Finnish (FIN) AF: 0.00972 AC: 103 AN: 10600

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.00563 AC: 383 AN: 67992

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

Alfa AF: 0.00251 Hom.: 0

Bravo AF: 0.00350

Asia WGS AF: 0.00116 AC: 4 AN: 3474

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	1	Focal segmental glomerulosclerosis (1)
-	1	-	Nephrotic syndrome, type 2 (1)
-	-	1	not specified (1)
-	-	1	NPHS2-related disorder (1)
-	-	1	Steroid-resistant nephrotic syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	1.4
DANN	Benign	0.59
PhyloP100		-1.2
PromoterAI		-0.095	Neutral
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: rs12123397; hg19: chr1-179544913;