chr16-23209862-A-G

Variant names:

• chr16-23209862-A-G
• rs5740
• NM_001039.4:c.1176+14A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001039.4(SCNN1G):​c.1176+14A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.801 in 1,598,884 control chromosomes in the GnomAD database, including 514,858 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.76 (44833 hom., cov: 32)
  • Exomes 𝑓: 0.81 (470025 hom.)
• Consequence: SCNN1G NM_001039.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:12
• Conservation: PhyloP100: -0.0830
• Publications: 20 publications found

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]

SCNN1G Gene-Disease associations (from GenCC):

• Liddle syndrome

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
• bronchiectasis with or without elevated sweat chloride 3

  Inheritance: AD Classification: STRONG Submitted by: PanelApp Australia
• Liddle syndrome 2

  Inheritance: AD Classification: STRONG, MODERATE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), Laboratory for Molecular Medicine
• pseudohypoaldosteronism, type IB1, autosomal recessive

  Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet

ENSG00000260741 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BP6: Variant 16-23209862-A-G is Benign according to our data. Variant chr16-23209862-A-G is described in ClinVar as Benign. ClinVar VariationId is 165176.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.858 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001039.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SCNN1G	NM_001039.4	MANE Select	c.1176+14A>G		intron	N/A	NP_001030.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SCNN1G	ENST00000300061.3	TSL:1 MANE Select	c.1176+14A>G		intron	N/A	ENSP00000300061.2
	ENSG00000260741	ENST00000563471.1	TSL:2	n.101+3142T>C		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.763 AC: 115962 AN: 151938 Hom.: 44799 Cov.: 32

Gnomad AFR AF: 0.649

Gnomad AMI AF: 0.806

Gnomad AMR AF: 0.831

Gnomad ASJ AF: 0.864

Gnomad EAS AF: 0.879

Gnomad SAS AF: 0.846

Gnomad FIN AF: 0.767

Gnomad MID AF: 0.858

Gnomad NFE AF: 0.795

Gnomad OTH AF: 0.795

GnomAD2 exomes AF: 0.814 AC: 204052 AN: 250684 AF XY: 0.815

Gnomad AFR exome AF: 0.647

Gnomad AMR exome AF: 0.898

Gnomad ASJ exome AF: 0.846

Gnomad EAS exome AF: 0.879

Gnomad FIN exome AF: 0.762

Gnomad NFE exome AF: 0.801

Gnomad OTH exome AF: 0.812

GnomAD4 exome AF: 0.805 AC: 1165060 AN: 1446828 Hom.: 470025 Cov.: 30 AF XY: 0.807 AC XY: 581610 AN XY: 720656

African (AFR) AF: 0.651 AC: 21551 AN: 33112

American (AMR) AF: 0.893 AC: 39914 AN: 44702

Ashkenazi Jewish (ASJ) AF: 0.850 AC: 22167 AN: 26068

East Asian (EAS) AF: 0.894 AC: 35414 AN: 39624

South Asian (SAS) AF: 0.847 AC: 72796 AN: 85952

European-Finnish (FIN) AF: 0.756 AC: 40354 AN: 53390

Middle Eastern (MID) AF: 0.832 AC: 4780 AN: 5748

European-Non Finnish (NFE) AF: 0.801 AC: 880031 AN: 1098298

Other (OTH) AF: 0.802 AC: 48053 AN: 59934

GnomAD4 genome AF: 0.763 AC: 116048 AN: 152056 Hom.: 44833 Cov.: 32 AF XY: 0.763 AC XY: 56674 AN XY: 74298

African (AFR) AF: 0.649 AC: 26902 AN: 41448

American (AMR) AF: 0.831 AC: 12712 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.864 AC: 3000 AN: 3472

East Asian (EAS) AF: 0.879 AC: 4528 AN: 5152

South Asian (SAS) AF: 0.847 AC: 4081 AN: 4818

European-Finnish (FIN) AF: 0.767 AC: 8095 AN: 10558

Middle Eastern (MID) AF: 0.857 AC: 252 AN: 294

European-Non Finnish (NFE) AF: 0.795 AC: 54067 AN: 67994

Other (OTH) AF: 0.794 AC: 1676 AN: 2112

Alfa AF: 0.791 Hom.: 166832

Bravo AF: 0.767

Asia WGS AF: 0.779 AC: 2706 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:12

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Feb 21, 2013

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

1176+14A>G in intron 7 of SCNN1G: This variant is not expected to have clinical significance because it is not located within the conserved splice consensus seq uence. It has been identified in 34.5% (1518/4394) of African American chromosom es from a broad population by the NHLBI Exome Sequencing Project (http://evs.gs. washington.edu/EVS; dbSNP rs5740).

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not provided Benign:3

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Nov 12, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Pseudohypoaldosteronism, type IB1, autosomal recessive Benign:2

Jan 13, 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.

Jul 15, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Liddle syndrome 2 Benign:2

Jan 13, 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.

Jul 15, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Bronchiectasis with or without elevated sweat chloride 3 Benign:1

Jul 15, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	1.1
DANN	Benign	0.26
PhyloP100		-0.083
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs5740; hg19: chr16-23221183;