16-23367958-C-T

Variant names:

• chr16-23367958-C-T
• rs250563
• NM_000336.3:c.879C>T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_000336.3(SCNN1B):​c.879C>T​(p.Phe293Phe) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0546 in 1,610,998 control chromosomes in the GnomAD database, including 3,889 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 0.098 (1203 hom., cov: 34)
  • Exomes 𝑓: 0.050 (2686 hom.)
• Consequence: SCNN1B NM_000336.3 splice_region, synonymous
• Scores: Splicing: ADA: 0.0004873
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: -1.72

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.72).
• BP6: Variant 16-23367958-C-T is Benign according to our data. Variant chr16-23367958-C-T is described in ClinVar as [Benign]. Clinvar id is 178802.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-23367958-C-T is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-1.72 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.215 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SCNN1B	NM_000336.3	c.879C>T	p.Phe293Phe	splice_region_variant, synonymous_variant	Exon 5 of 13	ENST00000343070.7	NP_000327.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SCNN1B	ENST00000343070.7	c.879C>T	p.Phe293Phe	splice_region_variant, synonymous_variant	Exon 5 of 13	1	NM_000336.3	ENSP00000345751.2

Frequencies

GnomAD3 genomes AF: 0.0976 AC: 14846 AN: 152096 Hom.: 1201 Cov.: 34

Gnomad AFR AF: 0.219

Gnomad AMI AF: 0.0198

Gnomad AMR AF: 0.0567

Gnomad ASJ AF: 0.0493

Gnomad EAS AF: 0.00115

Gnomad SAS AF: 0.0118

Gnomad FIN AF: 0.0940

Gnomad MID AF: 0.114

Gnomad NFE AF: 0.0509

Gnomad OTH AF: 0.0823

GnomAD3 exomes AF: 0.0563 AC: 14160 AN: 251486 Hom.: 733 AF XY: 0.0522 AC XY: 7100 AN XY: 135914

Gnomad AFR exome AF: 0.226

Gnomad AMR exome AF: 0.0384

Gnomad ASJ exome AF: 0.0480

Gnomad EAS exome AF: 0.000381

Gnomad SAS exome AF: 0.0149

Gnomad FIN exome AF: 0.0897

Gnomad NFE exome AF: 0.0520

Gnomad OTH exome AF: 0.0583

GnomAD4 exome AF: 0.0501 AC: 73153 AN: 1458784 Hom.: 2686 Cov.: 31 AF XY: 0.0489 AC XY: 35502 AN XY: 725988

Gnomad4 AFR exome AF: 0.231

Gnomad4 AMR exome AF: 0.0399

Gnomad4 ASJ exome AF: 0.0486

Gnomad4 EAS exome AF: 0.000101

Gnomad4 SAS exome AF: 0.0157

Gnomad4 FIN exome AF: 0.0835

Gnomad4 NFE exome AF: 0.0476

Gnomad4 OTH exome AF: 0.0552

GnomAD4 genome AF: 0.0976 AC: 14862 AN: 152214 Hom.: 1203 Cov.: 34 AF XY: 0.0969 AC XY: 7213 AN XY: 74428

Gnomad4 AFR AF: 0.219

Gnomad4 AMR AF: 0.0568

Gnomad4 ASJ AF: 0.0493

Gnomad4 EAS AF: 0.00116

Gnomad4 SAS AF: 0.0118

Gnomad4 FIN AF: 0.0940

Gnomad4 NFE AF: 0.0509

Gnomad4 OTH AF: 0.0814

Alfa AF: 0.0580 Hom.: 768

Bravo AF: 0.101

EpiCase AF: 0.0546

EpiControl AF: 0.0535

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:4

Jan 26, 2020

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 12, 2017

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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

- -

not specified Benign:2

Oct 18, 2013

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Phe293Phe in exon 05 of SCNN1B: This variant is not expected to have clinical s ignificance because it does not alter an amino acid residue and is not predicted to alter splicing (0/5 programs). It has been identified in 20% (915/4394) of A frican American chromosomes from a broad population by the NHLBI Exome Sequencin g Project (http://evs.gs.washington.edu/EVS; dbSNP rs250563). -

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Pseudohypoaldosteronism, type IB1, autosomal recessive Benign:1

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. -

Liddle syndrome 1 Benign:1

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. -

Bronchiectasis with or without elevated sweat chloride 1 Benign:1

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.72
CADD	Benign	1.3
DANN	Benign	0.65

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00049
dbscSNV1_RF	Benign	0.28
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: rs250563; hg19: chr16-23379279; COSMIC: COSV56304084;