rs137852707

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1PM2PP3PP5

The NM_000336.3(SCNN1B):​c.1858T>C​(p.Tyr620His) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Y620C) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Consequence

SCNN1B
NM_000336.3 missense

Scores

9
9
1

Clinical Significance

Pathogenic no assertion criteria provided P:1

Conservation

PhyloP100: 5.74
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]

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ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

PM1
In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 5 uncertain in NM_000336.3
PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.789
PP5
Variant 16-23380736-T-C is Pathogenic according to our data. Variant chr16-23380736-T-C is described in ClinVar as [Pathogenic]. Clinvar id is 8833.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
SCNN1BNM_000336.3 linkuse as main transcriptc.1858T>C p.Tyr620His missense_variant 13/13 ENST00000343070.7

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
SCNN1BENST00000343070.7 linkuse as main transcriptc.1858T>C p.Tyr620His missense_variant 13/131 NM_000336.3 P1P51168-1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
32
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Pathogenic
Submissions summary: Pathogenic:1
Revision: no assertion criteria provided
LINK: link

Submissions by phenotype

Liddle syndrome 1 Pathogenic:1
Pathogenic, no assertion criteria providedliterature onlyOMIMApr 01, 1996- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.96
BayesDel_addAF
Pathogenic
0.35
D
BayesDel_noAF
Pathogenic
0.26
CADD
Uncertain
25
DANN
Uncertain
1.0
DEOGEN2
Pathogenic
0.82
D;.;.;.
Eigen
Uncertain
0.45
Eigen_PC
Uncertain
0.49
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Uncertain
0.92
D;D;D;D
M_CAP
Uncertain
0.13
D
MetaRNN
Pathogenic
0.79
D;D;D;D
MetaSVM
Uncertain
0.16
D
MutationAssessor
Uncertain
2.8
M;.;.;.
MutationTaster
Benign
1.0
A;A;A;A
PrimateAI
Uncertain
0.77
T
PROVEAN
Uncertain
-3.9
D;D;D;D
REVEL
Pathogenic
0.76
Sift
Pathogenic
0.0
D;D;D;D
Sift4G
Pathogenic
0.0
D;D;D;D
Polyphen
1.0
D;.;.;.
Vest4
0.79
MutPred
0.59
Loss of phosphorylation at Y620 (P = 0.0205);.;.;.;
MVP
0.93
MPC
0.73
ClinPred
0.99
D
GERP RS
5.0
Varity_R
0.75
gMVP
0.67

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

Publications

LitVar

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

Other links and lift over

dbSNP: rs137852707; hg19: chr16-23392057; API