rs250563

chr16-23367958-C-Gchr16-23367958-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_000336.3(SCNN1B):c.879C>G(p.Phe293Leu) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000343 in 1,459,322 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. F293Y) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: SCNN1B NM_000336.3 missense, splice_region
• Scores: Splicing: ADA: 0.0009173
• Clinical Significance: Not reported in ClinVar
• 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 Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.904

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SCNN1B	NM_000336.3	c.879C>G	p.Phe293Leu	missense_variant, splice_region_variant	5/13	ENST00000343070.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SCNN1B	ENST00000343070.7	c.879C>G	p.Phe293Leu	missense_variant, splice_region_variant	5/13	1	NM_000336.3	P1

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD3 exomes AF: 0.0000119 AC: 3 AN: 251486 Hom.: 0 AF XY: 0.0000147 AC XY: 2 AN XY: 135914

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000980

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000343 AC: 5 AN: 1459322 Hom.: 0 Cov.: 31 AF XY: 0.00000413 AC XY: 3 AN XY: 726212

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000580

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 34

Bravo AF: 0.00000378

ExAC AF: 0.00000824 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Benign	-0.19
Cadd	Benign	7.4
Dann	Benign	0.96
DEOGEN2	Uncertain	0.45	T;.;.;.
Eigen	Benign	-0.85
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.046	N
LIST_S2	Uncertain	0.87	D;D;D;D
M_CAP	Benign	0.036	D
MetaRNN	Pathogenic	0.90	D;D;D;D
MetaSVM	Uncertain	-0.15	T
MutationAssessor	Uncertain	2.9	M;.;.;.
MutationTaster	Benign	0.10	P;P;P;P
PrimateAI	Uncertain	0.68	T
PROVEAN	Uncertain	-2.5	N;N;N;D
REVEL	Uncertain	0.43
Sift	Benign	0.039	D;T;T;D
Sift4G	Uncertain	0.017	D;D;D;D
Polyphen		1.0	D;.;.;.
Vest4		0.66
MutPred		0.60		Gain of disorder (P = 0.0893);.;Gain of disorder (P = 0.0893);.;
MVP		0.64
MPC		0.59
ClinPred		0.74	D
GERP RS		-7.9
Varity_R		0.43
gMVP		0.78

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00092
dbscSNV1_RF	Benign	0.10
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;