rs5723

Positions:

• chr16-23215466-C-G

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001039.4(SCNN1G):​c.1947C>G​(p.Leu649=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.206 in 1,608,242 control chromosomes in the GnomAD database, including 35,956 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.21 (3530 hom., cov: 32)
  • Exomes 𝑓: 0.21 (32426 hom.)
• Consequence: SCNN1G NM_001039.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:13
• Conservation: PhyloP100: 0.124

Genes affected

SCNN1G (HGNC:10602): (sodium channel epithelial 1 subunit gamma) 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 gamma subunit, and mutations in this gene have been associated with Liddle syndrome. [provided by RefSeq, Apr 2009]

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.78).
• BP6: Variant 16-23215466-C-G is Benign according to our data. Variant chr16-23215466-C-G is described in ClinVar as [Benign]. Clinvar id is 165177.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-23215466-C-G is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=0.124 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.242 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SCNN1G	NM_001039.4	c.1947C>G	p.Leu649=	synonymous_variant	13/13	ENST00000300061.3	NP_001030.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SCNN1G	ENST00000300061.3	c.1947C>G	p.Leu649=	synonymous_variant	13/13	1	NM_001039.4	ENSP00000300061	P1

Frequencies

GnomAD3 genomes AF: 0.212 AC: 32178 AN: 152018 Hom.: 3521 Cov.: 32

Gnomad AFR AF: 0.246

Gnomad AMI AF: 0.197

Gnomad AMR AF: 0.163

Gnomad ASJ AF: 0.227

Gnomad EAS AF: 0.0603

Gnomad SAS AF: 0.0742

Gnomad FIN AF: 0.231

Gnomad MID AF: 0.190

Gnomad NFE AF: 0.220

Gnomad OTH AF: 0.208

GnomAD3 exomes AF: 0.174 AC: 42641 AN: 244838 Hom.: 4396 AF XY: 0.172 AC XY: 22818 AN XY: 133026

Gnomad AFR exome AF: 0.254

Gnomad AMR exome AF: 0.0961

Gnomad ASJ exome AF: 0.233

Gnomad EAS exome AF: 0.0626

Gnomad SAS exome AF: 0.0806

Gnomad FIN exome AF: 0.231

Gnomad NFE exome AF: 0.215

Gnomad OTH exome AF: 0.199

GnomAD4 exome AF: 0.205 AC: 298707 AN: 1456106 Hom.: 32426 Cov.: 34 AF XY: 0.202 AC XY: 146193 AN XY: 724636

Gnomad4 AFR exome AF: 0.251

Gnomad4 AMR exome AF: 0.105

Gnomad4 ASJ exome AF: 0.233

Gnomad4 EAS exome AF: 0.0558

Gnomad4 SAS exome AF: 0.0845

Gnomad4 FIN exome AF: 0.223

Gnomad4 NFE exome AF: 0.221

Gnomad4 OTH exome AF: 0.206

GnomAD4 genome AF: 0.212 AC: 32216 AN: 152136 Hom.: 3530 Cov.: 32 AF XY: 0.208 AC XY: 15504 AN XY: 74394

Gnomad4 AFR AF: 0.246

Gnomad4 AMR AF: 0.162

Gnomad4 ASJ AF: 0.227

Gnomad4 EAS AF: 0.0601

Gnomad4 SAS AF: 0.0742

Gnomad4 FIN AF: 0.231

Gnomad4 NFE AF: 0.220

Gnomad4 OTH AF: 0.214

Alfa AF: 0.223 Hom.: 720

Bravo AF: 0.207

Asia WGS AF: 0.110 AC: 382 AN: 3478

EpiCase AF: 0.215

EpiControl AF: 0.209

ClinVar

Significance: Benign

Submissions summary: Benign:13

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Feb 21, 2013	Leu649Leu in exon 13 of SCNN1G: This variant is not expected to have clinical si gnificance because it does not alter an amino acid residue and is not located wi thin the splice consensus sequence. It has been identified in 25.2% (1107/4390) of African American chromosomes from a broad population by the NHLBI Exome Seque ncing Project (http://evs.gs.washington.edu/EVS; dbSNP rs5723). -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

not provided Benign:4

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 29, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 22, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jul 24, 2017	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Pseudohypoaldosteronism, type IB1, autosomal recessive Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 15, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 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. -

Liddle syndrome 2 Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 15, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 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. -

Bronchiectasis with or without elevated sweat chloride 3 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 15, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.78
CADD	Benign	0.51
DANN	Benign	0.57

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

Other links and lift over

dbSNP: rs5723; hg19: chr16-23226787; COSMIC: COSV55599716; COSMIC: COSV55599716;