16-23377193-C-A

Variant names:

• chr16-23377193-C-A
• rs149172890
• NM_000336.3:c.1299C>A

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_000336.3(SCNN1B):​c.1299C>A​(p.Ser433Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,461,850 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. S433S) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: SCNN1B NM_000336.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -1.49
• Publications: 0 publications found

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]

SCNN1B Gene-Disease associations (from GenCC):

• Liddle syndrome 1

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
• pseudohypoaldosteronism, type IB2, autosomal recessive

  Inheritance: AR Classification: DEFINITIVE Submitted by: Ambry Genetics
• bronchiectasis with or without elevated sweat chloride 1

  Inheritance: AD, SD Classification: STRONG, LIMITED Submitted by: PanelApp Australia, Ambry Genetics
• pseudohypoaldosteronism, type IB1, autosomal recessive

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

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.824

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SCNN1B	NM_000336.3	c.1299C>A	p.Ser433Arg	missense_variant	Exon 9 of 13	ENST00000343070.7	NP_000327.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SCNN1B	ENST00000343070.7	c.1299C>A	p.Ser433Arg	missense_variant	Exon 9 of 13	1	NM_000336.3	ENSP00000345751.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1461850 Hom.: 0 Cov.: 33 AF XY: 0.00000413 AC XY: 3 AN XY: 727224

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86248

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53414

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000360 AC: 4 AN: 1111992

Other (OTH) AF: 0.00 AC: 0 AN: 60396

GnomAD4 genome Cov.: 32

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Bronchiectasis with or without elevated sweat chloride 1;C5774255:Pseudohypoaldosteronism, type IB2, autosomal recessive;CN031472:Liddle syndrome 1 Uncertain:1

Apr 30, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.38
BayesDel_addAF	Benign	-0.10	T
BayesDel_noAF	Benign	-0.39
CADD	Benign	9.3
DANN	Benign	0.94
DEOGEN2	Benign	0.17	T;.;.;.
Eigen	Benign	-0.48
Eigen_PC	Benign	-0.67
FATHMM_MKL	Benign	0.035	N
LIST_S2	Benign	0.83	T;T;T;T
M_CAP	Benign	0.065	D
MetaRNN	Pathogenic	0.82	D;D;D;D
MetaSVM	Benign	-0.90	T
MutationAssessor	Benign	1.7	L;.;.;.
PhyloP100		-1.5
PrimateAI	Benign	0.46	T
PROVEAN	Benign	-1.5	N;N;N;N
REVEL	Uncertain	0.29
Sift	Benign	0.11	T;T;T;T
Sift4G	Uncertain	0.0040	D;D;D;D
Polyphen		0.93	P;.;.;.
Vest4		0.58
MutPred		0.65		Loss of catalytic residue at V434 (P = 0.1481);.;.;.;
MVP		0.76
MPC		0.38
ClinPred		0.72	D
GERP RS		0.47
Varity_R		0.16
gMVP		0.66
Mutation Taster		=83/17	polymorphism

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: rs149172890; hg19: chr16-23388514;