12-6355813-TG-T

Position:

• chr12-6355813-TG-T

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_001038.6(SCNN1A):​c.942delC​(p.Asn315fs) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: SCNN1A NM_001038.6 frameshift
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: -0.0300

Genes affected

SCNN1A (HGNC:10599): (sodium channel epithelial 1 subunit alpha) 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 alpha subunit, and mutations in this gene have been associated with pseudohypoaldosteronism type 1 (PHA1), a rare salt wasting disease resulting from target organ unresponsiveness to mineralocorticoids. Alternatively spliced transcript variants encoding different isoforms have been described for this gene. [provided by RefSeq, Apr 2009]

SCNN1A (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 12 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 12-6355813-TG-T is Pathogenic according to our data. Variant chr12-6355813-TG-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 504974.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SCNN1A	NM_001038.6	c.942delC	p.Asn315fs	frameshift_variant	5/13	ENST00000228916.7	NP_001029.1
SCNN1A	NM_001159576.2	c.1119delC	p.Asn374fs	frameshift_variant	4/12		NP_001153048.1
SCNN1A	NM_001159575.2	c.1011delC	p.Asn338fs	frameshift_variant	5/13		NP_001153047.1
LOC107984500	XR_007063191.1	n.*35delG		downstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SCNN1A	ENST00000228916.7	c.942delC	p.Asn315fs	frameshift_variant	5/13	1	NM_001038.6	ENSP00000228916.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Idiopathic bronchiectasis Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

May 20, 2016

The p.Asn374fs variant in SCNN1A has not been previously reported in individuals with pulmonary disease or in large population studies. This variant is predicte d to cause a frameshift, which alters the protein?s amino acid sequence beginnin g at position 374 and leads to a premature termination codon 16 amino acids down stream. This alteration is then predicted to lead to a truncated or absent prote in. Heterozygous loss of function of the SCNN1A gene is an established disease m echanism in individuals with pseudohypoaldosteronism which can include a pulmona ry phenotype. In summary, although additional studies are required to fully esta blish its clinical significance, the p.Asn374fs variant is likely pathogenic. -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1555112332; hg19: chr12-6464979;