Genetic Variant NPHS2:c.452-31T>C (chr1-179559792-A-G) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_014625.4(NPHS2):c.452-31T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0102 in 1,438,442 control chromosomes in the GnomAD database, including 1,196 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). There are indicators that this mutation may affect the branch point..

Frequency

Genomes: 𝑓 0.051 ( 657 hom., cov: 32)

Exomes 𝑓: 0.0053 ( 539 hom. )

Consequence

NPHS2
NM_014625.4 intron

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 1.32

Publications

5 publications found

Variant links:

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

NPHS2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

This position, referring to a specific DNA site, is a probable branch point but rather VUS (scored 4 / 10). The score ranges from 0 to 10, with values ≤3 considered benign and >5 classified as pathogenic. Computational evidence support a benign effect (BayesDel_noAF=-0.77).

BP6

Variant 1-179559792-A-G is Benign according to our data. Variant chr1-179559792-A-G is described in ClinVar as Benign. ClinVar VariationId is 1224998.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.176 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NPHS2	NM_014625.4 link	c.452-31T>C		intron_variant	Intron 3 of 7	ENST00000367615.9	NP_055440.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NPHS2	ENST00000367615.9 link	c.452-31T>C		intron_variant	Intron 3 of 7	1	NM_014625.4	ENSP00000356587.4
NPHS2	ENST00000367616.4 link	c.452-31T>C		intron_variant	Intron 3 of 6	1		ENSP00000356588.4

Frequencies

GnomAD3 genomes

AF:

0.0514

AC:

7816

AN:

152086

Hom.:

655

Cov.:

show subpopulations

Gnomad AFR

AF:

0.179

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0187

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000830

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00949

Gnomad NFE

AF:

0.000441

Gnomad OTH

AF:

0.0388

GnomAD2 exomes

AF:

0.0128

AC:

2119

AN:

165996

AF XY:

0.00915

show subpopulations

Gnomad AFR exome

AF:

0.184

Gnomad AMR exome

AF:

0.0109

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000385

Gnomad OTH exome

AF:

0.00624

GnomAD4 exome

AF:

0.00534

AC:

6867

AN:

1286238

Hom.:

539

Cov.:

AF XY:

0.00459

AC XY:

2944

AN XY:

641074

show subpopulations

African (AFR)

AF:

0.186

AC:

5469

AN:

29336

American (AMR)

AF:

0.0110

AC:

407

AN:

37048

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24478

East Asian (EAS)

AF:

0.00

AC:

AN:

35680

South Asian (SAS)

AF:

0.000504

AC:

AN:

77316

European-Finnish (FIN)

AF:

0.00

AC:

AN:

49266

Middle Eastern (MID)

AF:

0.00641

AC:

AN:

5456

European-Non Finnish (NFE)

AF:

0.000245

AC:

239

AN:

973644

Other (OTH)

AF:

0.0126

AC:

678

AN:

54014

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.497

Heterozygous variant carriers

303

606

908

1211

1514

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

166

332

498

664

830

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0515

AC:

7831

AN:

152204

Hom.:

657

Cov.:

AF XY:

0.0503

AC XY:

3747

AN XY:

74436

show subpopulations

African (AFR)

AF:

0.179

AC:

7427

AN:

41504

American (AMR)

AF:

0.0187

AC:

286

AN:

15294

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5184

South Asian (SAS)

AF:

0.000830

AC:

AN:

4818

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10612

Middle Eastern (MID)

AF:

0.0102

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000441

AC:

AN:

68006

Other (OTH)

AF:

0.0384

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

319

639

958

1278

1597

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

144

216

288

360

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0277

Hom.:

107

Bravo

AF:

0.0591

Asia WGS

AF:

0.00808

AC:

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

Jan 16, 2020

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.77

CADD

Benign

(source)

DANN

Benign

0.82

PhyloP100

1.3

BranchPoint Hunter

4.0

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over