16-23380574-C-T

Position:

• chr16-23380574-C-T

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1_Strong PM2 PP5_Very_Strong

The ENST00000343070.7(SCNN1B):​c.1696C>T​(p.Arg566Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000657 in 152,234 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency: Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
• Consequence: SCNN1B ENST00000343070.7 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:7
• Conservation: PhyloP100: 1.14

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 Pathogenic. Variant got 14 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. There are 15 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 16-23380574-C-T is Pathogenic according to our data. Variant chr16-23380574-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 8830.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SCNN1B	NM_000336.3	c.1696C>T	p.Arg566Ter	stop_gained	13/13	ENST00000343070.7	NP_000327.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SCNN1B	ENST00000343070.7	c.1696C>T	p.Arg566Ter	stop_gained	13/13	1	NM_000336.3	ENSP00000345751	P1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152234 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000941

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 32

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152234 Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1 AN XY: 74374

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0000941

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	Athena Diagnostics	Oct 15, 2021	This variant is expected to result in the loss of a functional protein. This variant results in a nonsense variant in the final exon of the gene which is not expected to trigger NMD, but which does eliminate the putatively important PY Motif. This variant was not reported in large, multi-ethnic, general populations (http://gnomad.broadinstitute.org). This variant segregates with disease in multiple families. Assessment of experimental evidence suggests this variant results in abnormal protein function. This variant has been shown in studies to eliminate the protein domain needed for proper regulation, and thus greatly increase current through the sodium channel (PMID: 7777572). -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 06, 2018	For these reasons, this variant has been classified as Pathogenic. This variant has been reported to result in constitutive hyperactivity of the SCNN1B sodium channel protein (PMID:7777572). This variant has been observed in several individuals with clinical features of Liddle syndrome (PMID: 27900368, 27896928, 26075967), and has been observed to segregate with Liddle syndrome in a family (PMID: 7954808). This variant is also known as p.Arg564* in the literature. ClinVar contains an entry for this variant (Variation ID: 8830). This variant is not present in population databases (ExAC no frequency). This sequence change results in a premature translational stop signal in the SCNN1B gene (p.Arg566*). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 75 amino acids of the SCNN1B protein. -
Pathogenic, criteria provided, single submitter	clinical testing	Clinical Genetics Laboratory, Skane University Hospital Lund	Feb 29, 2024	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Dec 28, 2023	Published functional studies demonstrate that the variant results in increased sodium channel activity (PMID: 7777572); Nonsense variant predicted to result in protein truncation, as the last 75 amino acids are lost, and other loss-of-function variants have been reported downstream in HGMD; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 27896928, 26075967, 9576123, 14645220, 28915228, 32561571, 24474657, 11478429, 10362597, 24093724, 7954808, 27900368, 7777572) -

Liddle syndrome 1 Pathogenic:2

Pathogenic, no assertion criteria provided	literature only	OMIM	Nov 04, 1994	- -
Pathogenic, criteria provided, single submitter	clinical testing	Lupski Lab, Baylor-Hopkins CMG, Baylor College of Medicine	Jun 23, 2016	- -

Bronchiectasis with or without elevated sweat chloride 1;C5774176:Pseudohypoaldosteronism, type IB1, autosomal recessive;CN031472:Liddle syndrome 1 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Jan 27, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.62	D
BayesDel_noAF	Pathogenic	0.31
CADD	Pathogenic	36
DANN	Uncertain	0.99
Eigen	Uncertain	0.21
Eigen_PC	Benign	-0.073
FATHMM_MKL	Benign	0.68	D
MutationTaster	Benign	1.0	A;A;A;A
Vest4		0.82
GERP RS		2.8

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs137852704; hg19: chr16-23391895; COSMIC: COSV56312145;