rs5738

Variant summary

Our verdict is Benign. Variant got -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. 12/19 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:9

Conservation

PhyloP100: 0.886

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -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 [Likely_benign]. Clinvar id is 8829.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-23189642-G-A is described in Lovd as [Benign].

BS2

High Homozygotes in GnomAd at 7 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SCNN1G	NM_001039.4 linkuse as main transcript	c.589G>A	p.Glu197Lys	missense_variant	3/13	ENST00000300061.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SCNN1G	ENST00000300061.3 linkuse as main transcript	c.589G>A	p.Glu197Lys	missense_variant	3/13	1	NM_001039.4	P1

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

GnomAD3 exomes

AF:

0.00503

AC:

1264

AN:

251464

Hom.:

AF XY:

0.00541

AC XY:

735

AN XY:

135920

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 SAS exome

AF:

0.0000980

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

Gnomad4 AFR exome

AF:

0.000866

Gnomad4 AMR exome

AF:

0.00559

Gnomad4 ASJ exome

AF:

0.00432

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.000162

Gnomad4 FIN exome

AF:

0.00133

Gnomad4 NFE exome

AF:

0.00967

Gnomad4 OTH exome

AF:

0.00785

GnomAD4 genome

AF:

0.00537

AC:

818

AN:

152318

Hom.:

Cov.:

AF XY:

0.00470

AC XY:

350

AN XY:

74474

show subpopulations

Gnomad4 AFR

AF:

0.00176

Gnomad4 AMR

AF:

0.00660

Gnomad4 ASJ

AF:

0.00576

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.000753

Gnomad4 NFE

AF:

0.00869

Gnomad4 OTH

AF:

0.00945

Alfa

AF:

0.00859

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:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:4

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Oct 01, 2023	SCNN1G: BP4, BS1 -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	May 15, 2020	This variant is associated with the following publications: (PMID: 25900089, 27264265, 28497567, 19462466, 18507830, 22933219) -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	May 02, 2018	- -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 22, 2024	- -

Autosomal recessive pseudohypoaldosteronism type 1

Benign:2

Benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
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. -

Bronchiectasis with or without elevated sweat chloride 3

Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

May 28, 2008

- -

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

- -

Bronchiectasis with or without elevated sweat chloride 3;C4748251:Liddle syndrome 2;C5774176:Autosomal recessive pseudohypoaldosteronism type 1

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Apr 07, 2022

- -

Liddle syndrome 2

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

0.074

BayesDel_addAF

Benign

-0.27

BayesDel_noAF

Benign

-0.15

Cadd

Benign

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

MutationTaster

Benign

0.11

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

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over