rs148985177

Positions:

• chr16-23215108-A-G

Variant summary

Our verdict is Likely benign. Variant got -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
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:6 B:2
• Conservation: PhyloP100: 6.81

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]

ACMG classification

Verdict is Likely_benign. Variant got -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 id is 318359.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=5}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SCNN1G	NM_001039.4	c.1589A>G	p.Asn530Ser	missense_variant	13/13	ENST00000300061.3	NP_001030.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SCNN1G	ENST00000300061.3	c.1589A>G	p.Asn530Ser	missense_variant	13/13	1	NM_001039.4	ENSP00000300061.2

Frequencies

GnomAD3 genomes AF: 0.000658 AC: 100 AN: 151946 Hom.: 0 Cov.: 32

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

GnomAD3 exomes AF: 0.000621 AC: 156 AN: 251320 Hom.: 0 AF XY: 0.000560 AC XY: 76 AN XY: 135832

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 SAS 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.: 0 Cov.: 32 AF XY: 0.000853 AC XY: 620 AN XY: 727240

Gnomad4 AFR exome AF: 0.000119

Gnomad4 AMR exome AF: 0.000246

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.000468

Gnomad4 NFE exome AF: 0.00111

Gnomad4 OTH exome AF: 0.000828

GnomAD4 genome AF: 0.000658 AC: 100 AN: 152064 Hom.: 0 Cov.: 32 AF XY: 0.000565 AC XY: 42 AN XY: 74342

Gnomad4 AFR AF: 0.000241

Gnomad4 AMR AF: 0.000196

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000377

Gnomad4 NFE AF: 0.00121

Gnomad4 OTH AF: 0.000475

Alfa AF: 0.000985 Hom.: 0

Bravo AF: 0.000563

TwinsUK AF: 0.00270 AC: 10

ALSPAC AF: 0.00104 AC: 4

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000698 AC: 6

ExAC AF: 0.000741 AC: 90

EpiCase AF: 0.000600

EpiControl AF: 0.000474

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:6 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Liddle syndrome 2 Pathogenic:1 Benign:1

Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	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. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Sep 27, 2018	- -

Bronchiectasis with or without elevated sweat chloride 3 Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Johns Hopkins Genomics, Johns Hopkins University	Jan 15, 2020	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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Baylor Genetics	Jun 30, 2019	This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. -

not provided Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jul 31, 2023	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. Experimental studies have shown that this missense change affects SCNN1G function (PMID: 12473862, 26537344). Advanced 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 at Invitae 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. ClinVar contains an entry for this variant (Variation ID: 318359). 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. This variant is present in population databases (rs148985177, gnomAD 0.1%), and has an allele count higher than expected for a pathogenic variant. 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). -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Apr 05, 2023	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) -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

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

May 02, 2024

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. -

SCNN1G-related disorder Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Undiagnosed Diseases Network, NIH

Apr 29, 2024

- -

Pseudohypoaldosteronism, type IB1, autosomal recessive Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

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	T
BayesDel_noAF	Benign	-0.29
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.26	T
Eigen	Uncertain	0.58
Eigen_PC	Uncertain	0.56
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.91	D
M_CAP	Benign	0.057	D
MetaRNN	Uncertain	0.49	T
MetaSVM	Benign	-0.47	T
MutationAssessor	Benign	2.0	M
PrimateAI	Uncertain	0.52	T
PROVEAN	Uncertain	-2.7	D
REVEL	Uncertain	0.49
Sift	Benign	0.11	T
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.86
MVP		0.80
MPC		0.71
ClinPred		0.060	T
GERP RS		5.2
Varity_R		0.27
gMVP		0.96

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

LitVar

Other links and lift over

dbSNP: rs148985177; hg19: chr16-23226429;