rs139111416

Variant names:

• chr1-179561293-G-A
• rs139111416
• NM_014625.4:c.447C>T

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_Moderate BP6 BP7 BS2

The NM_014625.4(NPHS2):​c.447C>T​(p.Gly149Gly) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00338 in 1,611,830 control chromosomes in the GnomAD database, including 13 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0027 (1 hom., cov: 33)
  • Exomes 𝑓: 0.0035 (12 hom.)
• Consequence: NPHS2 NM_014625.4 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:3
• Conservation: PhyloP100: -0.472
• Publications: 1 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 -8 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.43).
• BP6: Variant 1-179561293-G-A is Benign according to our data. Variant chr1-179561293-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 586185.
• BP7: Synonymous conserved (PhyloP=-0.472 with no splicing effect.
• BS2: High Homozygotes in GnomAdExome4 at 12 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NPHS2	NM_014625.4	MANE Select	c.447C>T	p.Gly149Gly	synonymous	Exon 3 of 8	NP_055440.1
	NPHS2	NM_001297575.2		c.447C>T	p.Gly149Gly	synonymous	Exon 3 of 7	NP_001284504.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NPHS2	ENST00000367615.9	TSL:1 MANE Select	c.447C>T	p.Gly149Gly	synonymous	Exon 3 of 8	ENSP00000356587.4
	NPHS2	ENST00000367616.4	TSL:1	c.447C>T	p.Gly149Gly	synonymous	Exon 3 of 7	ENSP00000356588.4

Frequencies

GnomAD3 genomes AF: 0.00274 AC: 416 AN: 152084 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.000990

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000589

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00491

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00454

Gnomad OTH AF: 0.00239

GnomAD2 exomes AF: 0.00251 AC: 630 AN: 251354 AF XY: 0.00249

Gnomad AFR exome AF: 0.000739

Gnomad AMR exome AF: 0.000839

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00522

Gnomad NFE exome AF: 0.00398

Gnomad OTH exome AF: 0.00375

GnomAD4 exome AF: 0.00345 AC: 5040 AN: 1459628 Hom.: 12 Cov.: 29 AF XY: 0.00335 AC XY: 2432 AN XY: 726324

African (AFR) AF: 0.000598 AC: 20 AN: 33444

American (AMR) AF: 0.000850 AC: 38 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.0000383 AC: 1 AN: 26120

East Asian (EAS) AF: 0.00 AC: 0 AN: 39670

South Asian (SAS) AF: 0.000104 AC: 9 AN: 86216

European-Finnish (FIN) AF: 0.00556 AC: 297 AN: 53416

Middle Eastern (MID) AF: 0.000521 AC: 3 AN: 5762

European-Non Finnish (NFE) AF: 0.00409 AC: 4537 AN: 1109956

Other (OTH) AF: 0.00224 AC: 135 AN: 60324

GnomAD4 genome AF: 0.00273 AC: 416 AN: 152202 Hom.: 1 Cov.: 33 AF XY: 0.00247 AC XY: 184 AN XY: 74414

African (AFR) AF: 0.000987 AC: 41 AN: 41528

American (AMR) AF: 0.000588 AC: 9 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.00 AC: 0 AN: 4814

European-Finnish (FIN) AF: 0.00491 AC: 52 AN: 10586

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

European-Non Finnish (NFE) AF: 0.00454 AC: 309 AN: 68010

Other (OTH) AF: 0.00237 AC: 5 AN: 2114

Alfa AF: 0.00328 Hom.: 1

Bravo AF: 0.00231

EpiCase AF: 0.00382

EpiControl AF: 0.00350

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

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	-0.43
CADD	Benign	9.5
DANN	Benign	0.69
PhyloP100		-0.47
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.14		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: rs139111416; hg19: chr1-179530428;