rs34618783

chr16-23380080-G-Achr16-23380080-G-Cchr16-23380080-G-T

Variant summary

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

The NM_000336.3(SCNN1B):c.1467-14G>A variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0279 in 1,610,206 control chromosomes in the GnomAD database, including 914 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.025 (74 hom., cov: 32)
  • Exomes 𝑓: 0.028 (840 hom.)
• Consequence: SCNN1B NM_000336.3 splice_polypyrimidine_tract, intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: -0.669

Genes affected

SCNN1B (HGNC:10600): (sodium channel epithelial 1 subunit beta) 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 beta subunit, and mutations in this gene have been associated with pseudohypoaldosteronism type 1 (PHA1), and Liddle syndrome. [provided by RefSeq, Apr 2009]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.71).
• BP6: Variant 16-23380080-G-A is Benign according to our data. Variant chr16-23380080-G-A is described in ClinVar as [Benign]. Clinvar id is 165170.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-23380080-G-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0669 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SCNN1B	NM_000336.3	c.1467-14G>A		splice_polypyrimidine_tract_variant, intron_variant		ENST00000343070.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SCNN1B	ENST00000343070.7	c.1467-14G>A		splice_polypyrimidine_tract_variant, intron_variant		1	NM_000336.3	P1

Frequencies

GnomAD3 genomes AF: 0.0250 AC: 3803 AN: 152044 Hom.: 74 Cov.: 32

Gnomad AFR AF: 0.00826

Gnomad AMI AF: 0.0297

Gnomad AMR AF: 0.0250

Gnomad ASJ AF: 0.0401

Gnomad EAS AF: 0.0728

Gnomad SAS AF: 0.0709

Gnomad FIN AF: 0.0409

Gnomad MID AF: 0.0285

Gnomad NFE AF: 0.0249

Gnomad OTH AF: 0.0292

GnomAD3 exomes AF: 0.0377 AC: 9485 AN: 251446 Hom.: 254 AF XY: 0.0395 AC XY: 5373 AN XY: 135904

Gnomad AFR exome AF: 0.00757

Gnomad AMR exome AF: 0.0337

Gnomad ASJ exome AF: 0.0429

Gnomad EAS exome AF: 0.0748

Gnomad SAS exome AF: 0.0732

Gnomad FIN exome AF: 0.0407

Gnomad NFE exome AF: 0.0268

Gnomad OTH exome AF: 0.0344

GnomAD4 exome AF: 0.0283 AC: 41203 AN: 1458044 Hom.: 840 Cov.: 30 AF XY: 0.0298 AC XY: 21646 AN XY: 725608

Gnomad4 AFR exome AF: 0.00709

Gnomad4 AMR exome AF: 0.0313

Gnomad4 ASJ exome AF: 0.0409

Gnomad4 EAS exome AF: 0.0677

Gnomad4 SAS exome AF: 0.0723

Gnomad4 FIN exome AF: 0.0386

Gnomad4 NFE exome AF: 0.0230

Gnomad4 OTH exome AF: 0.0295

GnomAD4 genome AF: 0.0250 AC: 3801 AN: 152162 Hom.: 74 Cov.: 32 AF XY: 0.0262 AC XY: 1949 AN XY: 74380

Gnomad4 AFR AF: 0.00821

Gnomad4 AMR AF: 0.0251

Gnomad4 ASJ AF: 0.0401

Gnomad4 EAS AF: 0.0730

Gnomad4 SAS AF: 0.0703

Gnomad4 FIN AF: 0.0409

Gnomad4 NFE AF: 0.0249

Gnomad4 OTH AF: 0.0289

Alfa AF: 0.0186 Hom.: 9

Bravo AF: 0.0231

Asia WGS AF: 0.0820 AC: 285 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Feb 21, 2013	1467-14G>A in intron 11 of SCNN1B: This variant is not expected to have clinical significance because it has been identified in 2.5% (214/8600) of European Amer ican chromosomes from a broad population by the NHLBI Exome Sequencing Project ( http://evs.gs.washington.edu/EVS; dbSNP rs34618783). -
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	PreventionGenetics, part of Exact Sciences	-	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 25, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 28, 2020	- -

Liddle syndrome 1 Benign:1

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. -

Autosomal recessive pseudohypoaldosteronism type 1 Benign:1

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 1 Benign:1

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.71
Cadd	Benign	9.2
Dann	Benign	0.76

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: rs34618783; hg19: chr16-23391401; COSMIC: COSV56304876;