rs148985177

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 0P and 1B. BP6

The NM_001039.4(SCNN1G):c.1589A>G(p.Asn530Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00088 in 1,613,944 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00090 ( 0 hom. )

Consequence

SCNN1G
NM_001039.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:7B:2

Conservation

PhyloP100: 6.81

Publications

12 publications found

Variant links:

Genes affected

SCNN1G (HGNC:10602): (sodium channel epithelial 1 subunit gamma) Nonvoltage-gated, amiloride-sensitive, sodium channels control fluid and electrolyte transport across epithelia in many organs. These channels are heteromeric complexes consisting of 3 subunits: alpha, beta, and gamma. This gene encodes the gamma subunit, and mutations in this gene have been associated with Liddle syndrome. [provided by RefSeq, Apr 2009]

SCNN1G Gene-Disease associations (from GenCC):

Liddle syndrome
Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
bronchiectasis with or without elevated sweat chloride 3
Inheritance: AD Classification: STRONG Submitted by: PanelApp Australia
Liddle syndrome 2
Inheritance: AD Classification: STRONG, MODERATE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), Laboratory for Molecular Medicine
pseudohypoaldosteronism, type IB1, autosomal recessive
Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet

SCNN1G links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -1 ACMG points.

BP6

Variant 16-23215108-A-G is Benign according to our data. Variant chr16-23215108-A-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 318359.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SCNN1G	NM_001039.4 link	c.1589A>G	p.Asn530Ser	missense_variant	Exon 13 of 13	ENST00000300061.3	NP_001030.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SCNN1G	ENST00000300061.3 link	c.1589A>G	p.Asn530Ser	missense_variant	Exon 13 of 13	1	NM_001039.4	ENSP00000300061.2

Frequencies

GnomAD3 genomes

AF:

0.000658

AC:

100

AN:

151946

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000242

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000197

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000377

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00121

Gnomad OTH

AF:

0.000480

GnomAD2 exomes

AF:

0.000621

AC:

156

AN:

251320

AF XY:

0.000560

show subpopulations

Gnomad AFR exome

AF:

0.000123

Gnomad AMR exome

AF:

0.000260

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000416

Gnomad NFE exome

AF:

0.00117

Gnomad OTH exome

AF:

0.000489

GnomAD4 exome

AF:

0.000904

AC:

1321

AN:

1461880

Hom.:

Cov.:

AF XY:

0.000853

AC XY:

620

AN XY:

727240

show subpopulations

African (AFR)

AF:

0.000119

AC:

AN:

33480

American (AMR)

AF:

0.000246

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.000468

AC:

AN:

53412

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00111

AC:

1231

AN:

1112008

Other (OTH)

AF:

0.000828

AC:

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.479

Heterozygous variant carriers

144

217

289

361

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

138

184

230

<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:

0.000658

AC:

100

AN:

152064

Hom.:

Cov.:

AF XY:

0.000565

AC XY:

AN XY:

74342

show subpopulations

African (AFR)

AF:

0.000241

AC:

AN:

41488

American (AMR)

AF:

0.000196

AC:

AN:

15272

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5152

South Asian (SAS)

AF:

0.00

AC:

AN:

4802

European-Finnish (FIN)

AF:

0.000377

AC:

AN:

10602

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00121

AC:

AN:

67968

Other (OTH)

AF:

0.000475

AC:

AN:

2106

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<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:

0.000902

Hom.:

Bravo

AF:

0.000563

TwinsUK

AF:

0.00270

AC:

ALSPAC

AF:

0.00104

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000698

AC:

ExAC

AF:

0.000741

AC:

EpiCase

AF:

0.000600

EpiControl

AF:

0.000474

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1Uncertain:7Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Liddle syndrome 2

Pathogenic:1Benign:1

Sep 27, 2018

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Bronchiectasis with or without elevated sweat chloride 3

Uncertain:2

Jun 30, 2019

Baylor Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. -

Jan 15, 2020

Johns Hopkins Genomics, Johns Hopkins University

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This SCNN1G variant has been reported in multiple patients with Liddle syndrome. A functional study demonstrates that this variant increases ENaC activity and, thus, also increases the channel open probability, which is consistent with an abnormally high sodium reabsorption in the distal nephron. This variant (rs148985177) has been identified in a large population dataset and the minor allele frequency is neither low enough to consider the variant rare (<0.1%) nor high enough to consider it a population polymorphism (>1%) within the non-Finnish European subpopulation (gnomAD: 169/129046 alleles; 0.13%, no homozygotes). A single submitter in ClinVar classifies this variant as likely benign. Of three bioinformatics tools queried, two predict that the substitution would be damaging, while one predicts that it would be tolerated and the asparagine residue at this position is highly evolutionarily conserved across all species assessed. Due to insufficient evidence, we consider the clinical significance of c.1589A>G to be uncertain at this time. -

not provided

Uncertain:2

Apr 05, 2023

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Observed in a young adult proband and parent with early onset hypertension and suspected Liddle syndrome, but was also present in a healthy blood donor and a control subject with low-normal blood pressure (Hiltunen et al., 2002); Published functional studies demonstrate a damaging gain-of-function effect, with N530S resulting in increased activity of epithelial sodium channels (Hiltunen et al., 2002; Boiko et al., 2015); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 35685915, 29534496, 29229744, 26537344, 31655555, 35661050, 30028216, 12473862) -

Nov 22, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces asparagine, which is neutral and polar, with serine, which is neutral and polar, at codon 530 of the SCNN1G protein (p.Asn530Ser). This variant is present in population databases (rs148985177, gnomAD 0.1%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with Liddle syndrome (PMID: 12473862). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 318359). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed for this missense variant. However, the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on SCNN1G protein function. Experimental studies have shown that this missense change affects SCNN1G function (PMID: 12473862, 26537344). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

not specified

Uncertain:1

May 02, 2024

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: SCNN1G c.1589A>G (p.Asn530Ser) results in a conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00062 in 251320 control chromosomes. This frequency does not allow any conclusion about variant significance. c.1589A>G has been reported in the literature in the heterozygous state in at least one family affected with Liddle syndrome where it segregated with disease (e.g. Hiltunen_2002). Experimental in vitro studies in CHO cells and xenopus oocytes showed that this variant increases ENaC activity compared to wildtype (e.g. Boiko_2015, Hiltunen_2002). The following publications have been ascertained in the context of this evaluation (PMID: 26537344, 12473862). ClinVar contains an entry for this variant (Variation ID: 318359). Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic. -

Bronchiectasis with or without elevated sweat chloride 3;C4748251:Liddle syndrome 2;C5774256:Pseudohypoaldosteronism, type IB3, autosomal recessive

Uncertain:1

May 03, 2024

Fulgent Genetics, Fulgent Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

SCNN1G-related disorder

Uncertain:1

Apr 29, 2024

Undiagnosed Diseases Network, NIH

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Pseudohypoaldosteronism, type IB1, autosomal recessive

Benign:1

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.14

BayesDel_addAF

Benign

-0.36

BayesDel_noAF

Benign

-0.29

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.26

Eigen

Uncertain

0.58

Eigen_PC

Uncertain

0.56

FATHMM_MKL

Uncertain

0.96

LIST_S2

Uncertain

0.91

M_CAP

Benign

0.057

MetaRNN

Uncertain

0.49

MetaSVM

Benign

-0.47

MutationAssessor

Benign

2.0

PhyloP100

6.8

PrimateAI

Uncertain

0.52

PROVEAN

Uncertain

-2.7

REVEL

Uncertain

0.49

Sift

Benign

0.11

Sift4G

Pathogenic

0.0

Polyphen

1.0

Vest4

0.86

MVP

0.80

MPC

0.71

ClinPred

0.060

GERP RS

5.2

Varity_R

0.27

gMVP

0.96

Mutation Taster

=19/81

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.040

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