rs13306653

Positions:

• chr16-23213095-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001039.4(SCNN1G):​c.1432-7G>A variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.205 in 1,610,694 control chromosomes in the GnomAD database, including 36,039 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.21 (3511 hom., cov: 31)
  • Exomes 𝑓: 0.20 (32528 hom.)
• Consequence: SCNN1G NM_001039.4 splice_region, splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.00002159
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:12
• Conservation: PhyloP100: 0.720

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]

(HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BP6: Variant 16-23213095-G-A is Benign according to our data. Variant chr16-23213095-G-A is described in ClinVar as [Benign]. Clinvar id is 165175.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-23213095-G-A is described in Lovd as [Benign].
• 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	UniProt
SCNN1G	NM_001039.4	c.1432-7G>A		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000300061.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SCNN1G	ENST00000300061.3	c.1432-7G>A		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_001039.4	P1
	ENST00000563471.1	n.10C>T		non_coding_transcript_exon_variant	1/4	2

Frequencies

GnomAD3 genomes AF: 0.212 AC: 32097 AN: 151716 Hom.: 3502 Cov.: 31

Gnomad AFR AF: 0.246

Gnomad AMI AF: 0.197

Gnomad AMR AF: 0.163

Gnomad ASJ AF: 0.226

Gnomad EAS AF: 0.0614

Gnomad SAS AF: 0.0738

Gnomad FIN AF: 0.232

Gnomad MID AF: 0.191

Gnomad NFE AF: 0.219

Gnomad OTH AF: 0.208

GnomAD3 exomes AF: 0.175 AC: 44036 AN: 251434 Hom.: 4563 AF XY: 0.172 AC XY: 23417 AN XY: 135894

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: 0.227

Gnomad NFE exome AF: 0.215

Gnomad OTH exome AF: 0.199

GnomAD4 exome AF: 0.205 AC: 298575 AN: 1458860 Hom.: 32528 Cov.: 33 AF XY: 0.201 AC XY: 146117 AN XY: 725874

Gnomad4 AFR exome AF: 0.251

Gnomad4 AMR exome AF: 0.105

Gnomad4 ASJ exome AF: 0.233

Gnomad4 EAS exome AF: 0.0559

Gnomad4 SAS exome AF: 0.0843

Gnomad4 FIN exome AF: 0.223

Gnomad4 NFE exome AF: 0.220

Gnomad4 OTH exome AF: 0.206

GnomAD4 genome AF: 0.212 AC: 32135 AN: 151834 Hom.: 3511 Cov.: 31 AF XY: 0.208 AC XY: 15463 AN XY: 74212

Gnomad4 AFR AF: 0.246

Gnomad4 AMR AF: 0.162

Gnomad4 ASJ AF: 0.226

Gnomad4 EAS AF: 0.0612

Gnomad4 SAS AF: 0.0739

Gnomad4 FIN AF: 0.232

Gnomad4 NFE AF: 0.219

Gnomad4 OTH AF: 0.215

Alfa AF: 0.214 Hom.: 7106

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:12

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Feb 21, 2013	1432-7G>A in intron 10 of SCNN1G: This variant is not expected to have clinical significance because it has been identified in 25.1% (1104/4394) of African Amer ican chromosomes from a broad population by the NHLBI Exome Sequencing Project ( http://evs.gs.washington.edu/EVS; dbSNP rs13306653). -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	Invitae	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	- -

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 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:2

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. -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 15, 2021	- -

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	-0.87
CADD	Benign	13
DANN	Benign	0.61

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000022
dbscSNV1_RF	Benign	0.0040
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: rs13306653; hg19: chr16-23224416;