dbSNP rs250563: SCNN1B:p.Phe293Leu (chr16-23367958-C-G) – ACMG Classification: Uncertain_significance (4 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP3_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. Synonymous variant affecting the same amino acid position (i.e. F293F) has been classified as Benign.

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

Variant links:

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 links:

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ACMG classification

Classification made for transcript

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 rank	MANE	Protein	UniProt
SCNN1B	NM_000336.3 link	c.879C>G	p.Phe293Leu	missense_variant, splice_region_variant	Exon 5 of 13	ENST00000343070.7	NP_000327.2	P51168-1B2R812

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SCNN1B	ENST00000343070.7 link	c.879C>G	p.Phe293Leu	missense_variant, splice_region_variant	Exon 5 of 13	1	NM_000336.3	ENSP00000345751.2		P51168-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.0000119

AC:

AN:

251486

Hom.:

AF XY:

0.0000147

AC XY:

AN XY:

135914

show subpopulations

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:

AN:

1459322

Hom.:

Cov.:

AF XY:

0.00000413

AC XY:

AN XY:

726212

show subpopulations

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.:

Bravo

AF:

0.00000378

ExAC

AF:

0.00000824

AC:

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

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

LIST_S2

Uncertain

0.87

D;D;D;D

M_CAP

Benign

0.036

MetaRNN

Pathogenic

0.90

D;D;D;D

MetaSVM

Uncertain

-0.15

MutationAssessor

Uncertain

2.9

M;.;.;.

PrimateAI

Uncertain

0.68

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

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

LitVar

Other links and lift over