rs5738

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_StrongBP6_Very_StrongBS2

The NM_001039.4(SCNN1G):c.589G>A(p.Glu197Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00777 in 1,614,198 control chromosomes in the GnomAD database, including 72 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E197Q) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0054 ( 7 hom., cov: 32)

Exomes 𝑓: 0.0080 ( 65 hom. )

Consequence

SCNN1G
NM_001039.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts P:1B:10

Conservation

PhyloP100: 0.886

Publications

24 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: Benign. The variant received -16 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.035057962).

BP6

Variant 16-23189642-G-A is Benign according to our data. Variant chr16-23189642-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 8829.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS2

High Homozygotes in GnomAd4 at 7 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SCNN1G	NM_001039.4 link	c.589G>A	p.Glu197Lys	missense_variant	Exon 3 of 13	ENST00000300061.3	NP_001030.2	P51170A5X2V1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SCNN1G	ENST00000300061.3 link	c.589G>A	p.Glu197Lys	missense_variant	Exon 3 of 13	1	NM_001039.4	ENSP00000300061.2		P51170

Frequencies

GnomAD3 genomes

AF:

0.00537

AC:

818

AN:

152200

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00176

Gnomad AMI

AF:

0.00329

Gnomad AMR

AF:

0.00661

Gnomad ASJ

AF:

0.00576

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000753

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.00869

Gnomad OTH

AF:

0.00955

GnomAD2 exomes

AF:

0.00503

AC:

1264

AN:

251464

AF XY:

0.00541

show subpopulations

Gnomad AFR exome

AF:

0.00123

Gnomad AMR exome

AF:

0.00520

Gnomad ASJ exome

AF:

0.00506

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00125

Gnomad NFE exome

AF:

0.00827

Gnomad OTH exome

AF:

0.00684

GnomAD4 exome

AF:

0.00802

AC:

11726

AN:

1461880

Hom.:

Cov.:

AF XY:

0.00785

AC XY:

5712

AN XY:

727242

show subpopulations

African (AFR)

AF:

0.000866

AC:

AN:

33480

American (AMR)

AF:

0.00559

AC:

250

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00432

AC:

113

AN:

26136

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39700

South Asian (SAS)

AF:

0.000162

AC:

AN:

86254

European-Finnish (FIN)

AF:

0.00133

AC:

AN:

53420

Middle Eastern (MID)

AF:

0.00295

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00967

AC:

10757

AN:

1112004

Other (OTH)

AF:

0.00785

AC:

474

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.485

Heterozygous variant carriers

647

1293

1940

2586

3233

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

418

836

1254

1672

2090

<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:

0.00537

AC:

818

AN:

152318

Hom.:

Cov.:

AF XY:

0.00470

AC XY:

350

AN XY:

74474

show subpopulations

African (AFR)

AF:

0.00176

AC:

AN:

41576

American (AMR)

AF:

0.00660

AC:

101

AN:

15302

Ashkenazi Jewish (ASJ)

AF:

0.00576

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5178

South Asian (SAS)

AF:

0.00

AC:

AN:

4818

European-Finnish (FIN)

AF:

0.000753

AC:

AN:

10622

Middle Eastern (MID)

AF:

0.00680

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00869

AC:

591

AN:

68028

Other (OTH)

AF:

0.00945

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

136

182

227

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

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:

0.00803

Hom.:

Bravo

AF:

0.00596

TwinsUK

AF:

0.00755

AC:

ALSPAC

AF:

0.00960

AC:

ESP6500AA

AF:

0.00250

AC:

ESP6500EA

AF:

0.00860

AC:

ExAC

AF:

0.00473

AC:

574

EpiCase

AF:

0.00916

EpiControl

AF:

0.0104

ClinVar

Significance: Benign/Likely benign

Submissions summary: Pathogenic:1Benign:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:5

May 02, 2018

Athena Diagnostics

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

- -

May 15, 2020

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 25900089, 27264265, 28497567, 19462466, 18507830, 22933219) -

May 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

SCNN1G: BP4, BS1 -

Jan 13, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Pseudohypoaldosteronism, type IB1, autosomal recessive

Benign:2

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. -

May 28, 2019

Mendelics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Bronchiectasis with or without elevated sweat chloride 3

Pathogenic:1

May 28, 2008

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

not specified

Benign:1

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Bronchiectasis with or without elevated sweat chloride 3;C4748251:Liddle syndrome 2;C5774176:Pseudohypoaldosteronism, type IB1, autosomal recessive

Benign:1

Apr 07, 2022

Fulgent Genetics, Fulgent Genetics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Liddle syndrome 2

Benign:1

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.074

BayesDel_addAF

Benign

-0.27

BayesDel_noAF

Benign

-0.15

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.15

Eigen

Benign

-0.96

Eigen_PC

Benign

-0.86

FATHMM_MKL

Benign

0.11

LIST_S2

Benign

0.60

MetaRNN

Benign

0.035

MetaSVM

Benign

-0.97

MutationAssessor

Benign

0.57

PhyloP100

0.89

PrimateAI

Benign

0.35

PROVEAN

Benign

-0.82

REVEL

Uncertain

0.41

Sift

Benign

0.36

Sift4G

Benign

0.60

Polyphen

0.0040

Vest4

0.14

MVP

0.51

MPC

0.24

ClinPred

0.0056

GERP RS

2.8

Varity_R

0.093

gMVP

0.52

Mutation Taster

=86/14

polymorphism

(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