16-23380584-C-T

Position:

chr16-23380584-C-T

Variant summary

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

The NM_000336.3(SCNN1B):c.1706C>T(p.Ala569Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000571 in 1,614,148 control chromosomes in the GnomAD database, including 8 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00060 ( 2 hom., cov: 33)

Exomes 𝑓: 0.00057 ( 6 hom. )

Consequence

SCNN1B
NM_000336.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:5

Conservation

PhyloP100: 3.15

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=0.0057277083).

BP6

Variant 16-23380584-C-T is Benign according to our data. Variant chr16-23380584-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 229239.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=2, Benign=3}.

BS1

Variant frequency is greater than expected in population mid. gnomad4_exome allele frequency = 0.000568 (830/1461816) while in subpopulation MID AF= 0.0139 (80/5766). AF 95% confidence interval is 0.0114. There are 6 homozygotes in gnomad4_exome. There are 439 alleles in male gnomad4_exome subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 2 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SCNN1B	NM_000336.3 linkuse as main transcript	c.1706C>T	p.Ala569Val	missense_variant	13/13	ENST00000343070.7	NP_000327.2	P51168-1B2R812

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SCNN1B	ENST00000343070.7 linkuse as main transcript	c.1706C>T	p.Ala569Val	missense_variant	13/13	1	NM_000336.3	ENSP00000345751.2		P51168-1

Frequencies

GnomAD3 genomes

AF:

0.000611

AC:

AN:

152214

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000965

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000851

Gnomad ASJ

AF:

0.00490

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00145

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.0190

Gnomad NFE

AF:

0.000632

Gnomad OTH

AF:

0.00143

GnomAD3 exomes

AF:

0.000701

AC:

176

AN:

251128

Hom.:

AF XY:

0.000810

AC XY:

110

AN XY:

135810

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000723

Gnomad ASJ exome

AF:

0.00546

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000490

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000573

Gnomad OTH exome

AF:

0.00261

GnomAD4 exome

AF:

0.000568

AC:

830

AN:

1461816

Hom.:

Cov.:

AF XY:

0.000604

AC XY:

439

AN XY:

727218

show subpopulations

Gnomad4 AFR exome

AF:

0.000627

Gnomad4 AMR exome

AF:

0.000894

Gnomad4 ASJ exome

AF:

0.00612

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.000661

Gnomad4 FIN exome

AF:

0.0000187

Gnomad4 NFE exome

AF:

0.000357

Gnomad4 OTH exome

AF:

0.00121

GnomAD4 genome

AF:

0.000597

AC:

AN:

152332

Hom.:

Cov.:

AF XY:

0.000631

AC XY:

AN XY:

74482

show subpopulations

Gnomad4 AFR

AF:

0.0000962

Gnomad4 AMR

AF:

0.000849

Gnomad4 ASJ

AF:

0.00490

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00124

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000632

Gnomad4 OTH

AF:

0.00142

Alfa

AF:

0.000816

Hom.:

Bravo

AF:

0.000620

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000930

AC:

ExAC

AF:

0.000708

AC:

Asia WGS

AF:

0.00144

AC:

AN:

3478

EpiCase

AF:

0.00104

EpiControl

AF:

0.00148

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:5

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Liddle syndrome 1

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Johns Hopkins Genomics, Johns Hopkins University	Dec 20, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 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. -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Mar 20, 2017

The p.Ala569Val variant in SCNN1B has been identified by our laboratory in one i ndividual with bronchiectasis. This variant has been identified in 0.1% (69/6637 8) of European chromosomes by the Exome Aggregation Consortium (ExAC, http://exa c.broadinstitute.org; dbSNP rs140927806). This variant has also been reported in ClinVar (Variant ID:229239). Computational prediction tools and conservation a nalysis do not provide strong support for or against an impact to the protein. I n summary, the clinical significance of the p.Ala569Val variant is uncertain. -

Pseudohypoaldosteronism, type IB1, autosomal recessive

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

SCNN1B-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Dec 08, 2022

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

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 22, 2023

- -

Bronchiectasis with or without elevated sweat chloride 1

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.088

BayesDel_addAF

Benign

-0.22

BayesDel_noAF

Benign

-0.18

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.30

T;.;.;.

Eigen

Benign

-0.40

Eigen_PC

Benign

-0.32

FATHMM_MKL

Uncertain

0.96

LIST_S2

Benign

0.81

T;T;T;T

M_CAP

Uncertain

0.087

MetaRNN

Benign

0.0057

T;T;T;T

MetaSVM

Benign

-0.63

MutationAssessor

Uncertain

2.7

M;.;.;.

PrimateAI

Benign

0.46

PROVEAN

Benign

-1.4

N;N;N;N

REVEL

Benign

0.25

Sift

Benign

0.12

T;T;T;T

Sift4G

Uncertain

0.037

D;D;D;D

Polyphen

0.34

B;.;.;.

Vest4

0.25

MVP

0.85

MPC

0.32

ClinPred

0.045

GERP RS

4.8

Varity_R

0.087

gMVP

0.63

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