16-23348708-G-A
Variant summary
Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PP3_Strong
The NM_000336.3(SCNN1B):c.109G>A(p.Gly37Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000105 in 1,613,940 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 Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
NM_000336.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 4 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.00000657 AC: 1AN: 152184Hom.: 0 Cov.: 31
GnomAD3 exomes AF: 0.0000239 AC: 6AN: 251114Hom.: 0 AF XY: 0.0000295 AC XY: 4AN XY: 135724
GnomAD4 exome AF: 0.0000109 AC: 16AN: 1461756Hom.: 0 Cov.: 32 AF XY: 0.00000825 AC XY: 6AN XY: 727160
GnomAD4 genome AF: 0.00000657 AC: 1AN: 152184Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0AN XY: 74350
ClinVar
Submissions by phenotype
Pseudohypoaldosteronism, type IB2, autosomal recessive Pathogenic:1
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Pseudohypoaldosteronism, type IB1, autosomal recessive Uncertain:1
The SCNN1B c.109G>A (p.Gly37Ser) variant has been reported in one study and was found in a homozygous state in two male cousins, both affected with pseudohypoaldosteronism type I, from a large consanguineous family of Arabic ancestry (Chang et al. 1996). Both parents of both affected individuals were unaffected and carried the variant in a heterozygous state. The p.Gly37Ser variant is absent from 160 unrelated control alleles and is reported at a frequency of 0.000135 in the European (non-Finnish) population of the Genome Aggregation Database. Amiloride sensitive sodium ion currents measured by 2-electrode voltage clamp in oocytes expressing wild type or p.Gly37Ser variant in the beta subunit revealed that the oocytes with the variant had an approximately 60% reduction of sodium channel activity (Chang et al. 1996). The decrease in macroscopic sodium currents is suggested due to a decrease in channel open probability, which would explain the disease pathophysiology (Grunder et al. 1997; Kucher et al. 2011). Based on the limited clinical evidence, the p.Gly37Ser variant is considered to be of unknown significance but suspicious for pathogenicity for autosomal recessive pseudohypoaldosteronism type I. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -
Liddle syndrome 1 Benign:1
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign. -
Bronchiectasis with or without elevated sweat chloride 1 Benign:1
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at