16-23380643-G-A

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_000336.3(SCNN1B):c.1765G>A(p.Gly589Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00253 in 1,613,440 control chromosomes in the GnomAD database, including 9 homozygotes. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0018 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0026 ( 9 hom. )

Consequence

SCNN1B
NM_000336.3 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: 0.388

Publications

9 publications found

Variant links:

Genes affected

SCNN1B (HGNC:10600): (sodium channel epithelial 1 subunit beta) 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 beta subunit, and mutations in this gene have been associated with pseudohypoaldosteronism type 1 (PHA1), and Liddle syndrome. [provided by RefSeq, Apr 2009]

SCNN1B Gene-Disease associations (from GenCC):

Liddle syndrome 1
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
pseudohypoaldosteronism, type IB2, autosomal recessive
Inheritance: AR Classification: DEFINITIVE Submitted by: Ambry Genetics
bronchiectasis with or without elevated sweat chloride 1
Inheritance: AD, SD Classification: STRONG, LIMITED Submitted by: PanelApp Australia, Ambry Genetics
pseudohypoaldosteronism, type IB1, autosomal recessive
Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae)
Liddle syndrome
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

SCNN1B 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=0.009487271).

BP6

Variant 16-23380643-G-A is Benign according to our data. Variant chr16-23380643-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 165171.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00177 (270/152342) while in subpopulation NFE AF = 0.00251 (171/68024). AF 95% confidence interval is 0.00221. There are 0 homozygotes in GnomAd4. There are 129 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAdExome4 at 9 AR,AD,SD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SCNN1B	NM_000336.3 link	c.1765G>A	p.Gly589Ser	missense_variant	Exon 13 of 13	ENST00000343070.7	NP_000327.2	P51168-1B2R812

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SCNN1B	ENST00000343070.7 link	c.1765G>A	p.Gly589Ser	missense_variant	Exon 13 of 13	1	NM_000336.3	ENSP00000345751.2		P51168-1

Frequencies

GnomAD3 genomes

AF:

0.00177

AC:

270

AN:

152224

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000675

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000458

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00565

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00251

Gnomad OTH

AF:

0.00191

GnomAD2 exomes

AF:

0.00189

AC:

470

AN:

249136

AF XY:

0.00187

show subpopulations

Gnomad AFR exome

AF:

0.000377

Gnomad AMR exome

AF:

0.000609

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00688

Gnomad NFE exome

AF:

0.00240

Gnomad OTH exome

AF:

0.00197

GnomAD4 exome

AF:

0.00261

AC:

3816

AN:

1461098

Hom.:

Cov.:

AF XY:

0.00249

AC XY:

1811

AN XY:

726842

show subpopulations

African (AFR)

AF:

0.000269

AC:

AN:

33470

American (AMR)

AF:

0.000671

AC:

AN:

44684

Ashkenazi Jewish (ASJ)

AF:

0.0000383

AC:

AN:

26090

East Asian (EAS)

AF:

0.00

AC:

AN:

39688

South Asian (SAS)

AF:

0.000383

AC:

AN:

86204

European-Finnish (FIN)

AF:

0.00748

AC:

398

AN:

53180

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5714

European-Non Finnish (NFE)

AF:

0.00290

AC:

3221

AN:

1111706

Other (OTH)

AF:

0.00205

AC:

124

AN:

60362

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.470

Heterozygous variant carriers

225

450

675

900

1125

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.00177

AC:

270

AN:

152342

Hom.:

Cov.:

AF XY:

0.00173

AC XY:

129

AN XY:

74476

show subpopulations

African (AFR)

AF:

0.000673

AC:

AN:

41590

American (AMR)

AF:

0.000457

AC:

AN:

15312

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5170

South Asian (SAS)

AF:

0.00

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.00565

AC:

AN:

10624

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00251

AC:

171

AN:

68024

Other (OTH)

AF:

0.00189

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.496

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00182

Hom.:

Bravo

AF:

0.00134

TwinsUK

AF:

0.00189

AC:

ALSPAC

AF:

0.00337

AC:

ESP6500AA

AF:

0.000683

AC:

ESP6500EA

AF:

0.00221

AC:

ExAC

AF:

0.00198

AC:

240

Asia WGS

AF:

0.000577

AC:

AN:

3478

EpiCase

AF:

0.00202

EpiControl

AF:

0.00231

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:1

Jul 01, 2014

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Gly589Ser in exon 13 of SCNN1B: This variant is not expected to have clinical si gnificance due to a lack of evolutionary conservation of the affected amino acid . Of note, 10 mammals carry a serine (Ser) at this position. Additionally, this variant has been identified in 19/8596 European American chromosomes and 3/4392 African American chromosomes by the NHLBI Exome Sequencing Project (http://evs. gs.washington.edu/EVS/; dbSNP rs61759926). -

Bronchiectasis with or without elevated sweat chloride 1;C5774176:Pseudohypoaldosteronism, type IB1, autosomal recessive;CN031472:Liddle syndrome 1

Benign:1

Nov 12, 2021

Fulgent Genetics, Fulgent Genetics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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. -

SCNN1B-related disorder

Benign:1

May 24, 2023

PreventionGenetics, part of Exact Sciences

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

not provided

Benign:1

Dec 24, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Liddle syndrome 1

Benign:1

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Bronchiectasis with or without elevated sweat chloride 1

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

0.075

BayesDel_addAF

Benign

-0.45

BayesDel_noAF

Benign

-0.42

CADD

Benign

1.0

(source)

DANN

Benign

0.89

DEOGEN2

Benign

0.16

T;.;.;.

Eigen

Benign

-1.1

Eigen_PC

Benign

-1.0

FATHMM_MKL

Benign

0.36

LIST_S2

Benign

0.77

T;T;T;T

M_CAP

Benign

0.031

MetaRNN

Benign

0.0095

T;T;T;T

MetaSVM

Benign

-0.98

MutationAssessor

Benign

1.5

L;.;.;.

PhyloP100

0.39

PrimateAI

Benign

0.30

PROVEAN

Benign

-0.51

N;N;N;N

REVEL

Benign

0.19

Sift

Benign

0.42

T;T;T;T

Sift4G

Benign

0.071

T;T;T;T

Polyphen

0.15

B;.;.;.

Vest4

0.074

MVP

0.59

MPC

0.17

ClinPred

0.0011

GERP RS

1.4

Varity_R

0.034

gMVP

0.64

Mutation Taster

=93/7

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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16-23380643-G-A

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