12-6375500-C-G

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BA1

The NM_001038.6(SCNN1A):c.-55+5G>C variant causes a splice donor 5th base, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0132 in 1,535,550 control chromosomes in the GnomAD database, including 827 homozygotes. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.027 (137 hom., cov: 32)
  • Exomes 𝑓: 0.012 (690 hom.)
• Consequence: SCNN1A NM_001038.6 splice_donor_5th_base, intron
• Scores: Splicing: ADA: 0.04595
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 3.41

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]

LTBR (HGNC:6718): (lymphotoxin beta receptor) This gene encodes a member of the tumor necrosis factor receptor superfamily. The major ligands of this receptor include lymphotoxin alpha/beta and tumor necrosis factor ligand superfamily member 14. The encoded protein plays a role in signalling during the development of lymphoid and other organs, lipid metabolism, immune response, and programmed cell death. Activity of this receptor has also been linked to carcinogenesis. Alternatively spliced transcript variants encoding multiple isoforms have been observed. [provided by RefSeq, Aug 2012]

ACMG classification

Verdict is Benign. Variant got -18 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.33).
• BP6: Variant 12-6375500-C-G is Benign according to our data. Variant chr12-6375500-C-G is described in ClinVar as [Benign]. Clinvar id is 310157.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.138 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SCNN1A	NM_001038.6	c.-55+5G>C		splice_donor_5th_base_variant, intron_variant		ENST00000228916.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SCNN1A	ENST00000228916.7	c.-55+5G>C		splice_donor_5th_base_variant, intron_variant		1	NM_001038.6	A2

Frequencies

GnomAD3 genomes AF: 0.0273 AC: 4158 AN: 152138 Hom.: 138 Cov.: 32

Gnomad AFR AF: 0.0522

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0188

Gnomad ASJ AF: 0.00835

Gnomad EAS AF: 0.147

Gnomad SAS AF: 0.0582

Gnomad FIN AF: 0.0385

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00281

Gnomad OTH AF: 0.0177

GnomAD4 exome AF: 0.0117 AC: 16148 AN: 1383294 Hom.: 690 Cov.: 32 AF XY: 0.0124 AC XY: 8483 AN XY: 682546

Gnomad4 AFR exome AF: 0.0594

Gnomad4 AMR exome AF: 0.0235

Gnomad4 ASJ exome AF: 0.00894

Gnomad4 EAS exome AF: 0.154

Gnomad4 SAS exome AF: 0.0469

Gnomad4 FIN exome AF: 0.0348

Gnomad4 NFE exome AF: 0.00151

Gnomad4 OTH exome AF: 0.0202

GnomAD4 genome AF: 0.0273 AC: 4158 AN: 152256 Hom.: 137 Cov.: 32 AF XY: 0.0300 AC XY: 2237 AN XY: 74452

Gnomad4 AFR AF: 0.0521

Gnomad4 AMR AF: 0.0187

Gnomad4 ASJ AF: 0.00835

Gnomad4 EAS AF: 0.147

Gnomad4 SAS AF: 0.0586

Gnomad4 FIN AF: 0.0385

Gnomad4 NFE AF: 0.00281

Gnomad4 OTH AF: 0.0180

Alfa AF: 0.00575 Hom.: 0

Bravo AF: 0.0290

Asia WGS AF: 0.101 AC: 351 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Bronchiectasis with or without elevated sweat chloride 2 Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 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

GeneDx

Sep 06, 2018

This variant is associated with the following publications: (PMID: 19462466) -

SCNN1A-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

May 22, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Autosomal recessive pseudohypoaldosteronism type 1 Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 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	-0.33
Cadd	Benign	19
Dann	Benign	0.94

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.046
dbscSNV1_RF	Benign	0.16
SpliceAI score (max)		0.64		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.64		Position offset: 5

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs13306617; hg19: chr12-6484666;