rs5739

chr16-23192369-C-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_001039.4(SCNN1G):c.636C>T(p.Ser212=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0212 in 1,613,838 control chromosomes in the GnomAD database, including 487 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.018 (52 hom., cov: 31)
  • Exomes 𝑓: 0.022 (435 hom.)
• Consequence: SCNN1G NM_001039.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -3.12

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=-0.81).
• BP6: Variant 16-23192369-C-T is Benign according to our data. Variant chr16-23192369-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 178805.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-23192369-C-T is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-3.12 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0176 (2673/152272) while in subpopulation NFE AF= 0.0264 (1798/68022). AF 95% confidence interval is 0.0254. There are 52 homozygotes in gnomad4. There are 1305 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 52 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SCNN1G	NM_001039.4	c.636C>T	p.Ser212=	synonymous_variant	4/13	ENST00000300061.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SCNN1G	ENST00000300061.3	c.636C>T	p.Ser212=	synonymous_variant	4/13	1	NM_001039.4	P1

Frequencies

GnomAD3 genomes AF: 0.0176 AC: 2676 AN: 152154 Hom.: 52 Cov.: 31

Gnomad AFR AF: 0.00403

Gnomad AMI AF: 0.00768

Gnomad AMR AF: 0.0142

Gnomad ASJ AF: 0.0233

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00705

Gnomad FIN AF: 0.0290

Gnomad MID AF: 0.0316

Gnomad NFE AF: 0.0264

Gnomad OTH AF: 0.0254

GnomAD3 exomes AF: 0.0192 AC: 4835 AN: 251460 Hom.: 74 AF XY: 0.0196 AC XY: 2669 AN XY: 135900

Gnomad AFR exome AF: 0.00332

Gnomad AMR exome AF: 0.0123

Gnomad ASJ exome AF: 0.0275

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.00670

Gnomad FIN exome AF: 0.0316

Gnomad NFE exome AF: 0.0268

Gnomad OTH exome AF: 0.0221

GnomAD4 exome AF: 0.0216 AC: 31615 AN: 1461566 Hom.: 435 Cov.: 32 AF XY: 0.0214 AC XY: 15542 AN XY: 727092

Gnomad4 AFR exome AF: 0.00350

Gnomad4 AMR exome AF: 0.0126

Gnomad4 ASJ exome AF: 0.0250

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00701

Gnomad4 FIN exome AF: 0.0352

Gnomad4 NFE exome AF: 0.0237

Gnomad4 OTH exome AF: 0.0203

GnomAD4 genome AF: 0.0176 AC: 2673 AN: 152272 Hom.: 52 Cov.: 31 AF XY: 0.0175 AC XY: 1305 AN XY: 74452

Gnomad4 AFR AF: 0.00402

Gnomad4 AMR AF: 0.0142

Gnomad4 ASJ AF: 0.0233

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00664

Gnomad4 FIN AF: 0.0290

Gnomad4 NFE AF: 0.0264

Gnomad4 OTH AF: 0.0251

Alfa AF: 0.0247 Hom.: 58

Bravo AF: 0.0162

Asia WGS AF: 0.00375 AC: 13 AN: 3478

EpiCase AF: 0.0261

EpiControl AF: 0.0266

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

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	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Feb 21, 2013	Ser212Ser in exon 4 of SCNN1G: This variant is not expected to have clinical sig nificance because it does not alter an amino acid residue and is not located wit hin the splice consensus sequence. It has been identified in 2.4% (207/8600) of European American chromosomes from a broad population by the NHLBI Exome Sequenc ing Project (http://evs.gs.washington.edu/EVS; dbSNP rs5739). -
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	Athena Diagnostics	Jan 16, 2018	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 29, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	May 16, 2020	- -

Liddle syndrome 2 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. -

Autosomal recessive pseudohypoaldosteronism type 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
BayesDel_noAF	Benign	-0.81
Cadd	Benign	5.6
Dann	Benign	0.86

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.090		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: rs5739; hg19: chr16-23203690;