rs5742912

chr12-6349184-A-G

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP3 BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001038.6(SCNN1A):c.1477T>C(p.Trp493Arg) variant causes a missense change. The variant allele was found at a frequency of 0.0206 in 1,614,044 control chromosomes in the GnomAD database, including 433 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.017 (47 hom., cov: 31)
  • Exomes 𝑓: 0.021 (386 hom.)
• Consequence: SCNN1A NM_001038.6 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts P:1 B:10
• Conservation: PhyloP100: 5.64

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]

LOC107984500 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -19 ACMG points.

• PP3: Multiple lines of computational evidence support a deleterious effect 6: AlphaMissense, BayesDel_noAF, Cadd, Eigen, MutationAssessor, PROVEAN [when max_spliceai, FATHMM_MKL, MetaRNN, MutationTaster was below the threshold]
• BP4: Computational evidence support a benign effect (MetaRNN=0.015588254).
• BP6: Variant 12-6349184-A-G is Benign according to our data. Variant chr12-6349184-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 9269.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-6349184-A-G is described in Lovd as [Benign]. Variant chr12-6349184-A-G is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.0167 (2542/152256) while in subpopulation AMR AF= 0.0255 (390/15294). AF 95% confidence interval is 0.0234. There are 47 homozygotes in gnomad4. There are 1201 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 47 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SCNN1A	NM_001038.6	c.1477T>C	p.Trp493Arg	missense_variant	10/13	ENST00000228916.7
LOC107984500	XR_007063191.1	n.87+917A>G		intron_variant, non_coding_transcript_variant
SCNN1A	NM_001159576.2	c.1654T>C	p.Trp552Arg	missense_variant	9/12
SCNN1A	NM_001159575.2	c.1546T>C	p.Trp516Arg	missense_variant	10/13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SCNN1A	ENST00000228916.7	c.1477T>C	p.Trp493Arg	missense_variant	10/13	1	NM_001038.6	A2

Frequencies

GnomAD3 genomes AF: 0.0167 AC: 2545 AN: 152138 Hom.: 47 Cov.: 31

Gnomad AFR AF: 0.00403

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0256

Gnomad ASJ AF: 0.0185

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.0191

Gnomad FIN AF: 0.0128

Gnomad MID AF: 0.0222

Gnomad NFE AF: 0.0241

Gnomad OTH AF: 0.0244

GnomAD3 exomes AF: 0.0192 AC: 4833 AN: 251454 Hom.: 66 AF XY: 0.0203 AC XY: 2752 AN XY: 135896

Gnomad AFR exome AF: 0.00394

Gnomad AMR exome AF: 0.0228

Gnomad ASJ exome AF: 0.0146

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0259

Gnomad FIN exome AF: 0.0134

Gnomad NFE exome AF: 0.0229

Gnomad OTH exome AF: 0.0238

GnomAD4 exome AF: 0.0210 AC: 30761 AN: 1461788 Hom.: 386 Cov.: 33 AF XY: 0.0217 AC XY: 15790 AN XY: 727202

Gnomad4 AFR exome AF: 0.00364

Gnomad4 AMR exome AF: 0.0223

Gnomad4 ASJ exome AF: 0.0160

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0247

Gnomad4 FIN exome AF: 0.0127

Gnomad4 NFE exome AF: 0.0226

Gnomad4 OTH exome AF: 0.0192

GnomAD4 genome AF: 0.0167 AC: 2542 AN: 152256 Hom.: 47 Cov.: 31 AF XY: 0.0161 AC XY: 1201 AN XY: 74454

Gnomad4 AFR AF: 0.00399

Gnomad4 AMR AF: 0.0255

Gnomad4 ASJ AF: 0.0185

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.0191

Gnomad4 FIN AF: 0.0128

Gnomad4 NFE AF: 0.0241

Gnomad4 OTH AF: 0.0242

Alfa AF: 0.0208 Hom.: 66

Bravo AF: 0.0169

TwinsUK AF: 0.0159 AC: 59

ALSPAC AF: 0.0244 AC: 94

ESP6500AA AF: 0.00522 AC: 23

ESP6500EA AF: 0.0237 AC: 204

ExAC AF: 0.0182 AC: 2214

Asia WGS AF: 0.0110 AC: 40 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Pathogenic:1 Benign:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:5

Likely benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Feb 24, 2016	The p.Trp552Arg variant in SCNN1A is prevalent in the general population with fr equencies up to 2.5% (413/16512) of South Asian chromosomes and 2.1% (1433/66734 ) of European chromosomes by the Exome Aggregation Consortium (ExAC, http://exac .broadinstitute.org; dbSNP rs5742912). While common, this variant has been claim ed to increase the risk of ischemic cerebrovascular events and cystic fibrosis-l ike clinical features up to 2 fold, particularly in carriers of a pathogenic CFT R variant, though these data are conflicting (Hsieh 2005, Azad 2009, Handschick 2012). In vitro functional studies provide some evidence that the p.Trp552Arg va riant may impact protein function, however these types of assays may not accurat ely reflect biological function. In summary, this variant is not expected to cau se disease on its own but a modifying role cannot be excluded. -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jun 01, 2015	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 30, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 05, 2021	This variant is associated with the following publications: (PMID: 26453628, 26668308, 26764160, 15734793, 21917531, 20194130, 19462466) -
Likely benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

Bronchiectasis with or without elevated sweat chloride 2 Pathogenic:1 Benign:1

Pathogenic, no assertion criteria provided	literature only	OMIM	Jul 01, 2009	- -
Likely 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). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Autosomal recessive pseudohypoaldosteronism type 1 Benign:1

Likely 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 determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Uncertain	0.024	T
BayesDel_noAF	Pathogenic	0.28
Cadd	Pathogenic	29
Dann	Uncertain	1.0
Eigen	Pathogenic	0.81
Eigen_PC	Pathogenic	0.73
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Benign	0.82	T;T;T;T
MetaRNN	Benign	0.016	T;T;T;T
MetaSVM	Uncertain	0.047	D
MutationTaster	Benign	1.0	A;A;A;A;A;A
PrimateAI	Uncertain	0.65	T
PROVEAN	Pathogenic	-13	D;D;D;D
REVEL	Uncertain	0.50
Sift	Pathogenic	0.0	D;D;D;D
Sift4G	Pathogenic	0.0	D;D;D;D
Polyphen		1.0	D;.;D;.
Vest4		0.42
MutPred		0.32		.;.;Gain of disorder (P = 0.0045);.;
MPC		0.75
ClinPred		0.093	T
GERP RS		5.2
Varity_R		0.93
gMVP		0.88

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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

Other links and lift over

dbSNP: rs5742912; hg19: chr12-6458350;