1-179552596-T-C

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_144696.6(AXDND1):c.3032-1916T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0393 in 1,611,690 control chromosomes in the GnomAD database, including 1,524 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.030 ( 97 hom., cov: 32)

Exomes 𝑓: 0.040 ( 1427 hom. )

Consequence

AXDND1
NM_144696.6 intron

Scores

Splicing: ADA: 0.0003180

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: -0.316

Publications

4 publications found

Variant links:

Genes affected

AXDND1 (HGNC:26564): (axonemal dynein light chain domain containing 1)

AXDND1 links:

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

Computational evidence support a benign effect (BayesDel_noAF=-0.76).

BP6

Variant 1-179552596-T-C is Benign according to our data. Variant chr1-179552596-T-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 260430.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0297 (4521/152122) while in subpopulation NFE AF = 0.0478 (3252/67980). AF 95% confidence interval is 0.0465. There are 97 homozygotes in GnomAd4. There are 2063 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 97 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AXDND1	NM_144696.6 link	c.3032-1916T>C		intron_variant	Intron 25 of 25	ENST00000367618.8	NP_653297.3
NPHS2	NM_014625.4 link	c.873+7A>G		splice_region_variant, intron_variant	Intron 7 of 7	ENST00000367615.9	NP_055440.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AXDND1	ENST00000367618.8 link	c.3032-1916T>C		intron_variant	Intron 25 of 25	1	NM_144696.6	ENSP00000356590.3
NPHS2	ENST00000367615.9 link	c.873+7A>G		splice_region_variant, intron_variant	Intron 7 of 7	1	NM_014625.4	ENSP00000356587.4

Frequencies

GnomAD3 genomes

AF:

0.0297

AC:

4520

AN:

152004

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00725

Gnomad AMI

AF:

0.0462

Gnomad AMR

AF:

0.0343

Gnomad ASJ

AF:

0.0300

Gnomad EAS

AF:

0.000385

Gnomad SAS

AF:

0.00872

Gnomad FIN

AF:

0.0133

Gnomad MID

AF:

0.0633

Gnomad NFE

AF:

0.0478

Gnomad OTH

AF:

0.0454

GnomAD2 exomes

AF:

0.0305

AC:

7600

AN:

249328

AF XY:

0.0314

show subpopulations

Gnomad AFR exome

AF:

0.00822

Gnomad AMR exome

AF:

0.0236

Gnomad ASJ exome

AF:

0.0283

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0162

Gnomad NFE exome

AF:

0.0488

Gnomad OTH exome

AF:

0.0356

GnomAD4 exome

AF:

0.0403

AC:

58816

AN:

1459568

Hom.:

1427

Cov.:

AF XY:

0.0397

AC XY:

28818

AN XY:

726082

show subpopulations

African (AFR)

AF:

0.00813

AC:

272

AN:

33442

American (AMR)

AF:

0.0251

AC:

1120

AN:

44638

Ashkenazi Jewish (ASJ)

AF:

0.0293

AC:

764

AN:

26086

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39678

South Asian (SAS)

AF:

0.0108

AC:

929

AN:

85968

European-Finnish (FIN)

AF:

0.0164

AC:

877

AN:

53336

Middle Eastern (MID)

AF:

0.0487

AC:

279

AN:

5730

European-Non Finnish (NFE)

AF:

0.0470

AC:

52217

AN:

1110394

Other (OTH)

AF:

0.0391

AC:

2357

AN:

60296

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.472

Heterozygous variant carriers

2513

5027

7540

10054

12567

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1824

3648

5472

7296

9120

<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:

0.0297

AC:

4521

AN:

152122

Hom.:

Cov.:

AF XY:

0.0277

AC XY:

2063

AN XY:

74378

show subpopulations

African (AFR)

AF:

0.00728

AC:

302

AN:

41510

American (AMR)

AF:

0.0343

AC:

523

AN:

15270

Ashkenazi Jewish (ASJ)

AF:

0.0300

AC:

104

AN:

3466

East Asian (EAS)

AF:

0.000386

AC:

AN:

5178

South Asian (SAS)

AF:

0.00872

AC:

AN:

4814

European-Finnish (FIN)

AF:

0.0133

AC:

141

AN:

10586

Middle Eastern (MID)

AF:

0.0612

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0478

AC:

3252

AN:

67980

Other (OTH)

AF:

0.0449

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.509

Heterozygous variant carriers

226

452

679

905

1131

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

116

174

232

290

<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:

0.0378

Hom.:

Bravo

AF:

0.0307

Asia WGS

AF:

0.00838

AC:

AN:

3476

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Nephrotic syndrome, type 2

Benign:2

Apr 11, 2023

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance:Likely benign

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 and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease.

not provided

Benign:2

Jan 29, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

not specified

Benign:1

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Steroid-resistant nephrotic syndrome

Benign:1

Nov 25, 2019

Natera, Inc.

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

Focal segmental glomerulosclerosis

Benign:1

Sep 02, 2022

Genome Diagnostics Laboratory, The Hospital for Sick Children

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

-0.76

CADD

Benign

0.78

(source)

DANN

Benign

0.73

PhyloP100

-0.32

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.00032

dbscSNV1_RF

Benign

0.064

SpliceAI score (max)

0.060

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