rs3741913

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_001038.6(SCNN1A):c.1853G>T(p.Cys618Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0059 in 1,603,002 control chromosomes in the GnomAD database, including 385 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.028 ( 186 hom., cov: 29)

Exomes 𝑓: 0.0036 ( 199 hom. )

Consequence

SCNN1A
NM_001038.6 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 0.583

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0019331872).

BP6

Variant 12-6348030-C-A is Benign according to our data. Variant chr12-6348030-C-A is described in ClinVar as [Benign]. Clinvar id is 194190.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-6348030-C-A is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0907 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
SCNN1A	NM_001038.6 linkuse as main transcript	c.1853G>T	p.Cys618Phe	missense_variant	13/13	ENST00000228916.7
SCNN1A	NM_001159576.2 linkuse as main transcript	c.2030G>T	p.Cys677Phe	missense_variant	12/12
SCNN1A	NM_001159575.2 linkuse as main transcript	c.1922G>T	p.Cys641Phe	missense_variant	13/13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SCNN1A	ENST00000228916.7 linkuse as main transcript	c.1853G>T	p.Cys618Phe	missense_variant	13/13	1	NM_001038.6	A2	P37088-1

Frequencies

GnomAD3 genomes

AF:

0.0276

AC:

4196

AN:

152102

Hom.:

185

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0930

Gnomad AMI

AF:

0.0154

Gnomad AMR

AF:

0.0119

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.0119

Gnomad SAS

AF:

0.00186

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.0190

Gnomad NFE

AF:

0.000441

Gnomad OTH

AF:

0.0202

GnomAD3 exomes

AF:

0.00706

AC:

1614

AN:

228504

Hom.:

AF XY:

0.00525

AC XY:

651

AN XY:

124008

show subpopulations

Gnomad AFR exome

AF:

0.0890

Gnomad AMR exome

AF:

0.00449

Gnomad ASJ exome

AF:

0.000105

Gnomad EAS exome

AF:

0.00366

Gnomad SAS exome

AF:

0.00307

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000337

Gnomad OTH exome

AF:

0.00492

GnomAD4 exome

AF:

0.00361

AC:

5239

AN:

1450782

Hom.:

199

Cov.:

AF XY:

0.00318

AC XY:

2292

AN XY:

720968

show subpopulations

Gnomad4 AFR exome

AF:

0.0955

Gnomad4 AMR exome

AF:

0.00524

Gnomad4 ASJ exome

AF:

0.0000387

Gnomad4 EAS exome

AF:

0.0242

Gnomad4 SAS exome

AF:

0.00193

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000257

Gnomad4 OTH exome

AF:

0.00704

GnomAD4 genome

AF:

0.0277

AC:

4211

AN:

152220

Hom.:

186

Cov.:

AF XY:

0.0266

AC XY:

1977

AN XY:

74422

show subpopulations

Gnomad4 AFR

AF:

0.0931

Gnomad4 AMR

AF:

0.0119

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.0120

Gnomad4 SAS

AF:

0.00166

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000441

Gnomad4 OTH

AF:

0.0200

Alfa

AF:

0.00585

Hom.:

Bravo

AF:

0.0315

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.000519

AC:

ESP6500AA

AF:

0.0895

AC:

394

ESP6500EA

AF:

0.000582

AC:

ExAC

AF:

0.00836

AC:

1014

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Feb 15, 2016	p.Cys677Phe in exon 12 of SCNN1A: This variant is not expected to have clinical significance because it is not located within the splice consensus sequence. It has been identified in 12.4% (695/5600) of African chromosomes, including 28 ho mozygotes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute. org; dbSNP rs3741913). -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Mar 05, 2015	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 16, 2019	This variant is associated with the following publications: (PMID: 16249274) -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 28, 2024	- -

Bronchiectasis with or without elevated sweat chloride 2

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

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 rule this variant out of causing disease. Therefore, this variant is classified as benign. -

Autosomal recessive pseudohypoaldosteronism type 1

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.075

BayesDel_addAF

Benign

-0.43

BayesDel_noAF

Benign

-0.33

Cadd

Benign

Dann

Uncertain

0.98

Eigen

Uncertain

0.30

Eigen_PC

Uncertain

0.24

FATHMM_MKL

Uncertain

0.82

LIST_S2

Benign

0.70

T;T;T;T

MetaRNN

Benign

0.0019

T;T;T;T

MetaSVM

Benign

-1.1

MutationTaster

Benign

1.0

D;N;N;N;N;N

PrimateAI

Benign

0.43

PROVEAN

Benign

-2.0

N;N;N;N

REVEL

Benign

0.24

Sift

Benign

0.48

T;T;T;T

Sift4G

Uncertain

0.037

D;D;D;D

Polyphen

1.0

D;.;D;.

Vest4

0.18

MVP

0.84

MPC

0.34

ClinPred

0.022

GERP RS

2.8

Varity_R

0.17

gMVP

0.43

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