rs11542844

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_001038.6(SCNN1A):c.1000G>A(p.Ala334Thr) variant causes a missense change. The variant allele was found at a frequency of 0.0643 in 1,613,752 control chromosomes in the GnomAD database, including 10,382 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar.

Frequency

Genomes: 𝑓 0.16 ( 4579 hom., cov: 32)

Exomes 𝑓: 0.054 ( 5803 hom. )

Consequence

SCNN1A
NM_001038.6 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: 4.32

Publications

33 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 -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0010077357).

BP6

Variant 12-6355415-C-T is Benign according to our data. Variant chr12-6355415-C-T is described in ClinVar as Benign. ClinVar VariationId is 165165.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.45 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
SCNN1A	NM_001038.6 link	c.1000G>A	p.Ala334Thr	missense_variant	Exon 6 of 13	ENST00000228916.7	NP_001029.1
SCNN1A	NM_001159576.2 link	c.1177G>A	p.Ala393Thr	missense_variant	Exon 5 of 12		NP_001153048.1
SCNN1A	NM_001159575.2 link	c.1069G>A	p.Ala357Thr	missense_variant	Exon 6 of 13		NP_001153047.1
LOC107984500	XR_007063191.1 link	n.297-110C>T		intron_variant	Intron 3 of 3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SCNN1A	ENST00000228916.7 link	c.1000G>A	p.Ala334Thr	missense_variant	Exon 6 of 13	1	NM_001038.6	ENSP00000228916.2

Frequencies

GnomAD3 genomes

AF:

0.164

AC:

24999

AN:

152128

Hom.:

4555

Cov.:

show subpopulations

Gnomad AFR

AF:

0.455

Gnomad AMI

AF:

0.00219

Gnomad AMR

AF:

0.0726

Gnomad ASJ

AF:

0.0354

Gnomad EAS

AF:

0.148

Gnomad SAS

AF:

0.0585

Gnomad FIN

AF:

0.105

Gnomad MID

AF:

0.0759

Gnomad NFE

AF:

0.0367

Gnomad OTH

AF:

0.117

GnomAD2 exomes

AF:

0.0794

AC:

19801

AN:

249434

AF XY:

0.0714

show subpopulations

Gnomad AFR exome

AF:

0.458

Gnomad AMR exome

AF:

0.0307

Gnomad ASJ exome

AF:

0.0459

Gnomad EAS exome

AF:

0.140

Gnomad FIN exome

AF:

0.0999

Gnomad NFE exome

AF:

0.0388

Gnomad OTH exome

AF:

0.0554

GnomAD4 exome

AF:

0.0539

AC:

78762

AN:

1461506

Hom.:

5803

Cov.:

AF XY:

0.0525

AC XY:

38171

AN XY:

727010

show subpopulations

African (AFR)

AF:

0.482

AC:

16134

AN:

33464

American (AMR)

AF:

0.0357

AC:

1594

AN:

44690

Ashkenazi Jewish (ASJ)

AF:

0.0437

AC:

1141

AN:

26128

East Asian (EAS)

AF:

0.146

AC:

5806

AN:

39690

South Asian (SAS)

AF:

0.0485

AC:

4185

AN:

86200

European-Finnish (FIN)

AF:

0.0974

AC:

5191

AN:

53300

Middle Eastern (MID)

AF:

0.0685

AC:

395

AN:

5768

European-Non Finnish (NFE)

AF:

0.0362

AC:

40226

AN:

1111886

Other (OTH)

AF:

0.0677

AC:

4090

AN:

60380

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.482

Heterozygous variant carriers

3818

7636

11454

15272

19090

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1786

3572

5358

7144

8930

<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:

0.165

AC:

25079

AN:

152246

Hom.:

4579

Cov.:

AF XY:

0.164

AC XY:

12214

AN XY:

74450

show subpopulations

African (AFR)

AF:

0.456

AC:

18918

AN:

41500

American (AMR)

AF:

0.0724

AC:

1108

AN:

15306

Ashkenazi Jewish (ASJ)

AF:

0.0354

AC:

123

AN:

3472

East Asian (EAS)

AF:

0.149

AC:

769

AN:

5176

South Asian (SAS)

AF:

0.0581

AC:

281

AN:

4834

European-Finnish (FIN)

AF:

0.105

AC:

1114

AN:

10606

Middle Eastern (MID)

AF:

0.0782

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0366

AC:

2492

AN:

68034

Other (OTH)

AF:

0.118

AC:

249

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

824

1647

2471

3294

4118

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

218

436

654

872

1090

<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:

0.0733

Hom.:

5009

Bravo

AF:

0.177

TwinsUK

AF:

0.0380

AC:

141

ALSPAC

AF:

0.0376

AC:

145

ESP6500AA

AF:

0.448

AC:

1975

ESP6500EA

AF:

0.0370

AC:

318

ExAC

AF:

0.0864

AC:

10495

Asia WGS

AF:

0.125

AC:

438

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Aug 06, 2019

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 19462466, 27582106) -

Jan 31, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Benign:2

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 21, 2013

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Ala393Thr in exon 5 of SCNN1A: This variant is not expected to have clinical sig nificance because it has been identified in 44.8% (1975/4406) of African America n chromosomes from a broad population by the NHLBI Exome Sequencing Project (htt p://evs.gs.washington.edu/EVS; dbSNP rs11542844). -

Bronchiectasis with or without elevated sweat chloride 2

Benign:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Pseudohypoaldosteronism, type IB1, autosomal recessive

Benign:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.048

BayesDel_addAF

Benign

-0.62

BayesDel_noAF

Benign

-0.51

CADD

Benign

(source)

DANN

Benign

0.92

DEOGEN2

Benign

0.091

.;.;T;T;.

Eigen

Benign

-0.86

Eigen_PC

Benign

-0.57

FATHMM_MKL

Benign

0.15

LIST_S2

Benign

0.46

T;T;T;T;T

MetaRNN

Benign

0.0010

T;T;T;T;T

MetaSVM

Benign

-0.92

MutationAssessor

Benign

-1.5

.;.;N;.;.

PhyloP100

4.3

PrimateAI

Uncertain

0.49

PROVEAN

Benign

1.6

N;N;N;N;N

REVEL

Benign

0.076

Sift

Benign

1.0

T;T;T;T;T

Sift4G

Benign

1.0

T;T;T;T;T

Polyphen

0.0020

B;.;B;.;.

Vest4

0.19

MPC

0.11

ClinPred

0.0044

GERP RS

3.7

Varity_R

0.11

gMVP

0.50

Mutation Taster

=98/2

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

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