16-23189488-C-T

Variant names:

• chr16-23189488-C-T
• rs62639702
• NM_001039.4:c.435C>T

Variant summary

Our verdict is Benign. Variant got -17 ACMG points: 0P and 17B. BP4_Strong BP6_Very_Strong BP7 BS2

The NM_001039.4(SCNN1G):​c.435C>T​(p.Ser145Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00753 in 1,614,156 control chromosomes in the GnomAD database, including 77 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0069 (8 hom., cov: 32)
  • Exomes 𝑓: 0.0076 (69 hom.)
• Consequence: SCNN1G NM_001039.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: -0.799

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 -17 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.79).
• BP6: Variant 16-23189488-C-T is Benign according to our data. Variant chr16-23189488-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 318347.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.799 with no splicing effect.
• BS2: High Homozygotes in GnomAd4 at 8 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SCNN1G	NM_001039.4	c.435C>T	p.Ser145Ser	synonymous_variant	Exon 3 of 13	ENST00000300061.3	NP_001030.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SCNN1G	ENST00000300061.3	c.435C>T	p.Ser145Ser	synonymous_variant	Exon 3 of 13	1	NM_001039.4	ENSP00000300061.2

Frequencies

GnomAD3 genomes AF: 0.00687 AC: 1046 AN: 152162 Hom.: 8 Cov.: 32

Gnomad AFR AF: 0.00748

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00327

Gnomad ASJ AF: 0.00202

Gnomad EAS AF: 0.00116

Gnomad SAS AF: 0.00952

Gnomad FIN AF: 0.00189

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.00864

Gnomad OTH AF: 0.00813

GnomAD3 exomes AF: 0.00660 AC: 1660 AN: 251470 Hom.: 9 AF XY: 0.00668 AC XY: 908 AN XY: 135912

Gnomad AFR exome AF: 0.00775

Gnomad AMR exome AF: 0.00425

Gnomad ASJ exome AF: 0.000992

Gnomad EAS exome AF: 0.00109

Gnomad SAS exome AF: 0.00918

Gnomad FIN exome AF: 0.00226

Gnomad NFE exome AF: 0.00859

Gnomad OTH exome AF: 0.00814

GnomAD4 exome AF: 0.00760 AC: 11110 AN: 1461876 Hom.: 69 Cov.: 43 AF XY: 0.00765 AC XY: 5560 AN XY: 727240

Gnomad4 AFR exome AF: 0.00702

Gnomad4 AMR exome AF: 0.00420

Gnomad4 ASJ exome AF: 0.00103

Gnomad4 EAS exome AF: 0.000554

Gnomad4 SAS exome AF: 0.00978

Gnomad4 FIN exome AF: 0.00258

Gnomad4 NFE exome AF: 0.00814

Gnomad4 OTH exome AF: 0.00878

GnomAD4 genome AF: 0.00690 AC: 1051 AN: 152280 Hom.: 8 Cov.: 32 AF XY: 0.00627 AC XY: 467 AN XY: 74454

Gnomad4 AFR AF: 0.00758

Gnomad4 AMR AF: 0.00327

Gnomad4 ASJ AF: 0.00202

Gnomad4 EAS AF: 0.00116

Gnomad4 SAS AF: 0.00953

Gnomad4 FIN AF: 0.00189

Gnomad4 NFE AF: 0.00864

Gnomad4 OTH AF: 0.00805

Alfa AF: 0.00779 Hom.: 2

Bravo AF: 0.00698

Asia WGS AF: 0.0180 AC: 64 AN: 3478

EpiCase AF: 0.00916

EpiControl AF: 0.0101

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:5

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Sep 17, 2018

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

SCNN1G: BP4, BP7, BS2 -

Jun 11, 2021

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

See Variant Classification Assertion Criteria. -

Jan 13, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Benign:1

Feb 21, 2013

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Ser145Ser in exon 3 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 0.9% (38/4394) of A frican American chromosomes from a broad population by the NHLBI Exome Sequencin g Project (http://evs.gs.washington.edu/EVS; dbSNP rs62639702). -

Bronchiectasis with or without elevated sweat chloride 3;C4748251:Liddle syndrome 2;C5774176:Pseudohypoaldosteronism, type IB1, autosomal recessive Benign:1

Jul 26, 2021

Fulgent Genetics, Fulgent Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Pseudohypoaldosteronism, type IB1, autosomal recessive Benign:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Liddle syndrome 2 Benign:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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	-0.79
CADD	Benign	2.0
DANN	Benign	0.52

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: rs62639702; hg19: chr16-23200809; COSMIC: COSV55599290;