12-6347577-G-A

Position:

• chr12-6347577-G-A

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_001038.6(SCNN1A):​c.*296C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00866 in 456,604 control chromosomes in the GnomAD database, including 31 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0082 (9 hom., cov: 33)
  • Exomes 𝑓: 0.0089 (22 hom.)
• Consequence: SCNN1A NM_001038.6 3_prime_UTR
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:3
• Conservation: PhyloP100: 0.185

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]

ACMG classification

Verdict is Benign. Variant got -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.75).
• BP6: Variant 12-6347577-G-A is Benign according to our data. Variant chr12-6347577-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 310126.We mark this variant Likely_benign, oryginal submissions are: {Benign=2, Likely_benign=1, Uncertain_significance=1}.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00822 (1252/152324) while in subpopulation NFE AF= 0.013 (885/68018). AF 95% confidence interval is 0.0123. There are 9 homozygotes in gnomad4. There are 575 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 9 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SCNN1A	NM_001038.6	c.*296C>T		3_prime_UTR_variant	13/13	ENST00000228916.7
SCNN1A	NM_001159575.2	c.*296C>T		3_prime_UTR_variant	13/13
SCNN1A	NM_001159576.2	c.*296C>T		3_prime_UTR_variant	12/12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SCNN1A	ENST00000228916.7	c.*296C>T		3_prime_UTR_variant	13/13	1	NM_001038.6	A2

Frequencies

GnomAD3 genomes AF: 0.00823 AC: 1252 AN: 152206 Hom.: 9 Cov.: 33

Gnomad AFR AF: 0.00253

Gnomad AMI AF: 0.0285

Gnomad AMR AF: 0.00569

Gnomad ASJ AF: 0.00375

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00269

Gnomad FIN AF: 0.00998

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0130

Gnomad OTH AF: 0.00717

GnomAD4 exome AF: 0.00888 AC: 2701 AN: 304280 Hom.: 22 Cov.: 0 AF XY: 0.00851 AC XY: 1338 AN XY: 157234

Gnomad4 AFR exome AF: 0.00229

Gnomad4 AMR exome AF: 0.00450

Gnomad4 ASJ exome AF: 0.00321

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00379

Gnomad4 FIN exome AF: 0.00871

Gnomad4 NFE exome AF: 0.0118

Gnomad4 OTH exome AF: 0.00870

GnomAD4 genome AF: 0.00822 AC: 1252 AN: 152324 Hom.: 9 Cov.: 33 AF XY: 0.00772 AC XY: 575 AN XY: 74488

Gnomad4 AFR AF: 0.00253

Gnomad4 AMR AF: 0.00569

Gnomad4 ASJ AF: 0.00375

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00269

Gnomad4 FIN AF: 0.00998

Gnomad4 NFE AF: 0.0130

Gnomad4 OTH AF: 0.00710

Alfa AF: 0.00519 Hom.: 0

Bravo AF: 0.00744

Asia WGS AF: 0.00115 AC: 4 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2023	SCNN1A: BS1, BS2 -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 06, 2019	See Variant Classification Assertion Criteria. -

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.75
CADD	Benign	9.5
DANN	Benign	0.83

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

Other links and lift over

dbSNP: rs55981728; hg19: chr12-6456743;