rs35731153

Positions:

chr16-23348844-C-G

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_000336.3(SCNN1B):c.245C>G(p.Ser82Cys) variant causes a missense change. The variant allele was found at a frequency of 0.00718 in 1,614,162 control chromosomes in the GnomAD database, including 63 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0044 ( 3 hom., cov: 31)

Exomes 𝑓: 0.0075 ( 60 hom. )

Consequence

SCNN1B
NM_000336.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:1B:14

Conservation

PhyloP100: 5.83

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.018293321).

BP6

Variant 16-23348844-C-G is Benign according to our data. Variant chr16-23348844-C-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 8844.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Benign=8, Uncertain_significance=1}. Variant chr16-23348844-C-G is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00445 (677/152288) while in subpopulation NFE AF= 0.00685 (466/68034). AF 95% confidence interval is 0.00634. There are 3 homozygotes in gnomad4. There are 304 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 3 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SCNN1B	NM_000336.3 linkuse as main transcript	c.245C>G	p.Ser82Cys	missense_variant	2/13	ENST00000343070.7	NP_000327.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SCNN1B	ENST00000343070.7 linkuse as main transcript	c.245C>G	p.Ser82Cys	missense_variant	2/13	1	NM_000336.3	ENSP00000345751	P1	P51168-1

Frequencies

GnomAD3 genomes

AF:

0.00446

AC:

679

AN:

152170

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00164

Gnomad AMI

AF:

0.00329

Gnomad AMR

AF:

0.00281

Gnomad ASJ

AF:

0.00951

Gnomad EAS

AF:

0.00116

Gnomad SAS

AF:

0.000829

Gnomad FIN

AF:

0.00301

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.00685

Gnomad OTH

AF:

0.0105

GnomAD3 exomes

AF:

0.00476

AC:

1193

AN:

250642

Hom.:

AF XY:

0.00466

AC XY:

631

AN XY:

135520

show subpopulations

Gnomad AFR exome

AF:

0.00117

Gnomad AMR exome

AF:

0.00260

Gnomad ASJ exome

AF:

0.00714

Gnomad EAS exome

AF:

0.000707

Gnomad SAS exome

AF:

0.00281

Gnomad FIN exome

AF:

0.00370

Gnomad NFE exome

AF:

0.00710

Gnomad OTH exome

AF:

0.00506

GnomAD4 exome

AF:

0.00746

AC:

10905

AN:

1461874

Hom.:

Cov.:

AF XY:

0.00719

AC XY:

5230

AN XY:

727240

show subpopulations

Gnomad4 AFR exome

AF:

0.000986

Gnomad4 AMR exome

AF:

0.00255

Gnomad4 ASJ exome

AF:

0.00700

Gnomad4 EAS exome

AF:

0.000781

Gnomad4 SAS exome

AF:

0.00308

Gnomad4 FIN exome

AF:

0.00414

Gnomad4 NFE exome

AF:

0.00870

Gnomad4 OTH exome

AF:

0.00608

GnomAD4 genome

AF:

0.00445

AC:

677

AN:

152288

Hom.:

Cov.:

AF XY:

0.00408

AC XY:

304

AN XY:

74464

show subpopulations

Gnomad4 AFR

AF:

0.00164

Gnomad4 AMR

AF:

0.00281

Gnomad4 ASJ

AF:

0.00951

Gnomad4 EAS

AF:

0.00116

Gnomad4 SAS

AF:

0.000830

Gnomad4 FIN

AF:

0.00301

Gnomad4 NFE

AF:

0.00685

Gnomad4 OTH

AF:

0.00947

Alfa

AF:

0.00644

Hom.:

Bravo

AF:

0.00465

TwinsUK

AF:

0.00971

AC:

ALSPAC

AF:

0.00908

AC:

ESP6500AA

AF:

0.00319

AC:

ESP6500EA

AF:

0.00802

AC:

ExAC

AF:

0.00479

AC:

581

Asia WGS

AF:

0.00346

AC:

AN:

3478

EpiCase

AF:

0.00687

EpiControl

AF:

0.00652

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1Uncertain:1Benign:14

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Bronchiectasis with or without elevated sweat chloride 1

Pathogenic:1Uncertain:1Benign:3

Pathogenic, no assertion criteria provided	literature only	OMIM	May 28, 2008	- -
Uncertain significance, criteria provided, single submitter	reference population	Soonchunhyang University Bucheon Hospital, Soonchunhyang University Medical Center	Mar 18, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Johns Hopkins Genomics, Johns Hopkins University	Oct 21, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Mar 06, 2018	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. -
Benign, criteria provided, single submitter	clinical testing	Mendelics	Aug 22, 2023	- -

not provided

Benign:5

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2024	SCNN1B: BS2 -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Dec 11, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Nov 13, 2023	- -
Likely benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -

not specified

Benign:2

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Nov 26, 2014	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 01, 2016	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Liddle syndrome 1

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Molecular Genetics, Royal Melbourne Hospital	Apr 07, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Mar 06, 2018	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

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Mar 06, 2018

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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

SCNN1B-related disorder

Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jan 15, 2020

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

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.52

BayesDel_addAF

Benign

-0.13

BayesDel_noAF

Uncertain

0.040

CADD

Pathogenic

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.71

D;.;.;.

Eigen

Pathogenic

0.73

Eigen_PC

Pathogenic

0.69

FATHMM_MKL

Uncertain

0.86

LIST_S2

Uncertain

0.86

D;D;D;D

M_CAP

Benign

0.059

MetaRNN

Benign

0.018

T;T;T;T

MetaSVM

Uncertain

-0.13

MutationAssessor

Pathogenic

3.0

M;.;.;.

MutationTaster

Benign

1.0

A;A;A;A

PrimateAI

Uncertain

0.53

PROVEAN

Uncertain

-3.9

D;D;D;D

REVEL

Uncertain

0.53

Sift

Uncertain

0.0010

D;D;D;D

Sift4G

Uncertain

0.0060

D;D;D;D

Polyphen

1.0

D;.;.;.

Vest4

0.59

MVP

0.95

MPC

0.62

ClinPred

0.024

GERP RS

5.0

Varity_R

0.56

gMVP

0.77

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