rs5742912

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 1P and 20B. PP3BP4_StrongBP6_Very_StrongBS1BS2

The NM_001038.6(SCNN1A):c.1477T>C(p.Trp493Arg) variant causes a missense change. The variant allele was found at a frequency of 0.0206 in 1,614,044 control chromosomes in the GnomAD database, including 433 homozygotes. In-silico tool predicts 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. W493G) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.017 ( 47 hom., cov: 31)

Exomes 𝑓: 0.021 ( 386 hom. )

Consequence

SCNN1A
NM_001038.6 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts P:1B:11

Conservation

PhyloP100: 5.64

Publications

42 publications found

Variant links:

Genes affected

SCNN1A (HGNC:10599): (sodium channel epithelial 1 subunit alpha) 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 alpha subunit, and mutations in this gene have been associated with pseudohypoaldosteronism type 1 (PHA1), a rare salt wasting disease resulting from target organ unresponsiveness to mineralocorticoids. Alternatively spliced transcript variants encoding different isoforms have been described for this gene. [provided by RefSeq, Apr 2009]

SCNN1A Gene-Disease associations (from GenCC):

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

SCNN1A links:

LOC107984500 (HGNC:):

LOC107984500 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -19 ACMG points.

PP3

Multiple lines of computational evidence support a deleterious effect 6: AlphaMissense, BayesDel_noAF, Cadd, Eigen, MutationAssessor, PROVEAN [when max_spliceai, FATHMM_MKL, MetaRNN, MutationTaster was below the threshold]

BP4

Computational evidence support a benign effect (MetaRNN=0.015588254).

BP6

Variant 12-6349184-A-G is Benign according to our data. Variant chr12-6349184-A-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 9269.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.0167 (2542/152256) while in subpopulation AMR AF = 0.0255 (390/15294). AF 95% confidence interval is 0.0234. There are 47 homozygotes in GnomAd4. There are 1201 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 47 AR,Unknown,AD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SCNN1A	NM_001038.6 link	c.1477T>C	p.Trp493Arg	missense_variant	Exon 10 of 13	ENST00000228916.7	NP_001029.1	P37088-1
SCNN1A	NM_001159576.2 link	c.1654T>C	p.Trp552Arg	missense_variant	Exon 9 of 12		NP_001153048.1	P37088-2
SCNN1A	NM_001159575.2 link	c.1546T>C	p.Trp516Arg	missense_variant	Exon 10 of 13		NP_001153047.1	P37088-6
LOC107984500	XR_007063191.1 link	n.87+917A>G		intron_variant	Intron 1 of 3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SCNN1A	ENST00000228916.7 link	c.1477T>C	p.Trp493Arg	missense_variant	Exon 10 of 13	1	NM_001038.6	ENSP00000228916.2		P37088-1

Frequencies

GnomAD3 genomes

AF:

0.0167

AC:

2545

AN:

152138

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00403

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0256

Gnomad ASJ

AF:

0.0185

Gnomad EAS

AF:

0.000192

Gnomad SAS

AF:

0.0191

Gnomad FIN

AF:

0.0128

Gnomad MID

AF:

0.0222

Gnomad NFE

AF:

0.0241

Gnomad OTH

AF:

0.0244

GnomAD2 exomes

AF:

0.0192

AC:

4833

AN:

251454

AF XY:

0.0203

show subpopulations

Gnomad AFR exome

AF:

0.00394

Gnomad AMR exome

AF:

0.0228

Gnomad ASJ exome

AF:

0.0146

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0134

Gnomad NFE exome

AF:

0.0229

Gnomad OTH exome

AF:

0.0238

GnomAD4 exome

AF:

0.0210

AC:

30761

AN:

1461788

Hom.:

386

Cov.:

AF XY:

0.0217

AC XY:

15790

AN XY:

727202

show subpopulations

African (AFR)

AF:

0.00364

AC:

122

AN:

33480

American (AMR)

AF:

0.0223

AC:

999

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.0160

AC:

418

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.0247

AC:

2129

AN:

86252

European-Finnish (FIN)

AF:

0.0127

AC:

677

AN:

53416

Middle Eastern (MID)

AF:

0.0235

AC:

135

AN:

5738

European-Non Finnish (NFE)

AF:

0.0226

AC:

25122

AN:

1111954

Other (OTH)

AF:

0.0192

AC:

1159

AN:

60388

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.479

Heterozygous variant carriers

1845

3689

5534

7378

9223

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

918

1836

2754

3672

4590

<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:

0.0167

AC:

2542

AN:

152256

Hom.:

Cov.:

AF XY:

0.0161

AC XY:

1201

AN XY:

74454

show subpopulations

African (AFR)

AF:

0.00399

AC:

166

AN:

41570

American (AMR)

AF:

0.0255

AC:

390

AN:

15294

Ashkenazi Jewish (ASJ)

AF:

0.0185

AC:

AN:

3468

East Asian (EAS)

AF:

0.000193

AC:

AN:

5188

South Asian (SAS)

AF:

0.0191

AC:

AN:

4820

European-Finnish (FIN)

AF:

0.0128

AC:

136

AN:

10598

Middle Eastern (MID)

AF:

0.0204

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0241

AC:

1636

AN:

68002

Other (OTH)

AF:

0.0242

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

121

242

362

483

604

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

112

140

<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:

0.0210

Hom.:

137

Bravo

AF:

0.0169

TwinsUK

AF:

0.0159

AC:

ALSPAC

AF:

0.0244

AC:

ESP6500AA

AF:

0.00522

AC:

ESP6500EA

AF:

0.0237

AC:

204

ExAC

AF:

0.0182

AC:

2214

Asia WGS

AF:

0.0110

AC:

AN:

3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Pathogenic:1Benign:11

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:5

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Feb 24, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.Trp552Arg variant in SCNN1A is prevalent in the general population with fr equencies up to 2.5% (413/16512) of South Asian chromosomes and 2.1% (1433/66734 ) of European chromosomes by the Exome Aggregation Consortium (ExAC, http://exac .broadinstitute.org; dbSNP rs5742912). While common, this variant has been claim ed to increase the risk of ischemic cerebrovascular events and cystic fibrosis-l ike clinical features up to 2 fold, particularly in carriers of a pathogenic CFT R variant, though these data are conflicting (Hsieh 2005, Azad 2009, Handschick 2012). In vitro functional studies provide some evidence that the p.Trp552Arg va riant may impact protein function, however these types of assays may not accurat ely reflect biological function. In summary, this variant is not expected to cau se disease on its own but a modifying role cannot be excluded. -

Jun 01, 2015

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:4

Jan 28, 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

- -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Apr 05, 2021

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 26453628, 26668308, 26764160, 15734793, 21917531, 20194130, 19462466) -

Bronchiectasis with or without elevated sweat chloride 2

Pathogenic:1Benign:1

Jul 01, 2009

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). 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. -

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). 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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.99

BayesDel_addAF

Uncertain

0.024

BayesDel_noAF

Pathogenic

0.28

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.68

.;.;D;.

Eigen

Pathogenic

0.81

Eigen_PC

Pathogenic

0.73

FATHMM_MKL

Uncertain

0.97

LIST_S2

Benign

0.82

T;T;T;T

MetaRNN

Benign

0.016

T;T;T;T

MetaSVM

Uncertain

0.047

MutationAssessor

Pathogenic

3.2

.;.;M;.

PhyloP100

5.6

PrimateAI

Uncertain

0.65

PROVEAN

Pathogenic

-13

D;D;D;D

REVEL

Uncertain

0.50

Sift

Pathogenic

0.0

D;D;D;D

Sift4G

Pathogenic

0.0

D;D;D;D

Polyphen

1.0

D;.;D;.

Vest4

0.42

MutPred

0.32

.;.;Gain of disorder (P = 0.0045);.;

MPC

0.75

ClinPred

0.093

GERP RS

5.2

Varity_R

0.93

gMVP

0.88

Mutation Taster

=82/18

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

Splicevardb

2.0

SpliceAI score (max)

0.010

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