12-6375606-G-A

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS1

The NM_001159575.2(SCNN1A):c.16-769C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00045 in 1,320,854 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.00029 (0 hom., cov: 30)
  • Exomes 𝑓: 0.00047 (0 hom.)
• Consequence: SCNN1A NM_001159575.2 intron
• Clinical Significance: Likely benign criteria provided, single submitter B:2
• Conservation: PhyloP100: -1.69

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 -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 12-6375606-G-A is Benign according to our data. Variant chr12-6375606-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 310161.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4_exome allele frequency = 0.000471 (551/1169152) while in subpopulation NFE AF= 0.00056 (498/889978). AF 95% confidence interval is 0.000519. There are 0 homozygotes in gnomad4_exome. There are 256 alleles in male gnomad4_exome subpopulation. Median coverage is 42. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SCNN1A	NM_001159575.2	c.16-769C>T		intron_variant
LTBR	NM_001270987.2	c.39+12G>A		intron_variant
LTBR	NM_001414309.1	c.39+12G>A		intron_variant
SCNN1A	NM_001038.6			upstream_gene_variant		ENST00000228916.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SCNN1A	ENST00000228916.7			upstream_gene_variant		1	NM_001038.6	A2

Frequencies

GnomAD3 genomes AF: 0.000290 AC: 44 AN: 151582 Hom.: 0 Cov.: 30

Gnomad AFR AF: 0.000169

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000386

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000381

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000443

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000210 AC: 24 AN: 114110 Hom.: 0 AF XY: 0.000239 AC XY: 15 AN XY: 62662

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000319

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000113

Gnomad SAS exome AF: 0.0000971

Gnomad FIN exome AF: 0.000418

Gnomad NFE exome AF: 0.000282

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000471 AC: 551 AN: 1169152 Hom.: 0 Cov.: 42 AF XY: 0.000440 AC XY: 256 AN XY: 581318

Gnomad4 AFR exome AF: 0.000135

Gnomad4 AMR exome AF: 0.000243

Gnomad4 ASJ exome AF: 0.0000940

Gnomad4 EAS exome AF: 0.0000595

Gnomad4 SAS exome AF: 0.000120

Gnomad4 FIN exome AF: 0.000317

Gnomad4 NFE exome AF: 0.000560

Gnomad4 OTH exome AF: 0.000357

GnomAD4 genome AF: 0.000290 AC: 44 AN: 151702 Hom.: 0 Cov.: 30 AF XY: 0.000283 AC XY: 21 AN XY: 74170

Gnomad4 AFR AF: 0.000169

Gnomad4 AMR AF: 0.0000654

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000387

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000381

Gnomad4 NFE AF: 0.000443

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000718 Hom.: 0

Bravo AF: 0.000276

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, single submitter

Submissions by phenotype

Autosomal recessive pseudohypoaldosteronism type 1 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Bronchiectasis with or without elevated sweat chloride 1 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
Cadd	Benign	4.7
Dann	Benign	0.89

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs72645138; hg19: chr12-6484772;