12-6354776-G-T
Variant summary
Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4_StrongBP6
The NM_001038.6(SCNN1A):c.1216C>A(p.Leu406Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000286 in 1,613,932 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
NM_001038.6 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -5 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
SCNN1A | NM_001038.6 | c.1216C>A | p.Leu406Ile | missense_variant | 7/13 | ENST00000228916.7 | |
LOC107984500 | XR_007063191.1 | n.297-749G>T | intron_variant, non_coding_transcript_variant | ||||
SCNN1A | NM_001159576.2 | c.1393C>A | p.Leu465Ile | missense_variant | 6/12 | ||
SCNN1A | NM_001159575.2 | c.1285C>A | p.Leu429Ile | missense_variant | 7/13 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
SCNN1A | ENST00000228916.7 | c.1216C>A | p.Leu406Ile | missense_variant | 7/13 | 1 | NM_001038.6 | A2 |
Frequencies
GnomAD3 genomes AF: 0.000290 AC: 44AN: 151984Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.000354 AC: 89AN: 251486Hom.: 1 AF XY: 0.000258 AC XY: 35AN XY: 135918
GnomAD4 exome AF: 0.000286 AC: 418AN: 1461830Hom.: 0 Cov.: 32 AF XY: 0.000274 AC XY: 199AN XY: 727220
GnomAD4 genome AF: 0.000289 AC: 44AN: 152102Hom.: 0 Cov.: 32 AF XY: 0.000269 AC XY: 20AN XY: 74346
ClinVar
Submissions by phenotype
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Sep 02, 2015 | Variant classified as Uncertain Significance - Favor Benign. The p.Leu465Ile var iant in SCNN1A has not been previously reported in individuals with pulmonary di sease, but has been identified in 33/66732 European chromosomes by the Exome Agg regation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs149484264). C omputational prediction tools and conservation analysis suggest that the p.Leu46 5Ile variant may not impact the protein, though this information is not predicti ve enough to rule out pathogenicity. In summary, while the clinical significance of the p.Leu465Ile variant is uncertain, these data suggest that it is more lik ely to be benign. - |
Inborn genetic diseases Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Sep 27, 2022 | The c.1216C>A (p.L406I) alteration is located in exon 7 (coding exon 6) of the SCNN1A gene. This alteration results from a C to A substitution at nucleotide position 1216, causing the leucine (L) at amino acid position 406 to be replaced by an isoleucine (I). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. - |
Autosomal recessive pseudohypoaldosteronism type 1 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jan 13, 2018 | This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. - |
Bronchiectasis with or without elevated sweat chloride 2 Benign:1
Benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jan 13, 2018 | This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. - |
not provided Benign:1
Benign, criteria provided, single submitter | clinical testing | Invitae | Jun 21, 2023 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at