12-6375605-C-T

Position:

• chr12-6375605-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001159575.2(SCNN1A):​c.16-768G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00282 in 1,473,904 control chromosomes in the GnomAD database, including 95 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.014 (49 hom., cov: 30)
  • Exomes 𝑓: 0.0016 (46 hom.)
• Consequence: SCNN1A NM_001159575.2 intron
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.367

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.56).
• BP6: Variant 12-6375605-C-T is Benign according to our data. Variant chr12-6375605-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 310160.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0141 (2060/146104) while in subpopulation AFR AF= 0.0474 (1904/40194). AF 95% confidence interval is 0.0456. There are 49 homozygotes in gnomad4. There are 998 alleles in male gnomad4 subpopulation. Median coverage is 30. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 49 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SCNN1A	NM_001159575.2	c.16-768G>A		intron_variant
LTBR	NM_001270987.2	c.39+11C>T		intron_variant
LTBR	NM_001414309.1	c.39+11C>T		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: 0.0141 AC: 2058 AN: 145990 Hom.: 49 Cov.: 30

Gnomad AFR AF: 0.0475

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00756

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000394

Gnomad SAS AF: 0.000445

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00641

Gnomad NFE AF: 0.000200

Gnomad OTH AF: 0.0126

GnomAD3 exomes AF: 0.00265 AC: 259 AN: 97890 Hom.: 3 AF XY: 0.00210 AC XY: 114 AN XY: 54226

Gnomad AFR exome AF: 0.0397

Gnomad AMR exome AF: 0.00299

Gnomad ASJ exome AF: 0.000170

Gnomad EAS exome AF: 0.000272

Gnomad SAS exome AF: 0.000110

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000279

Gnomad OTH exome AF: 0.00205

GnomAD4 exome AF: 0.00157 AC: 2091 AN: 1327800 Hom.: 46 Cov.: 57 AF XY: 0.00139 AC XY: 904 AN XY: 652040

Gnomad4 AFR exome AF: 0.0475

Gnomad4 AMR exome AF: 0.00330

Gnomad4 ASJ exome AF: 0.0000441

Gnomad4 EAS exome AF: 0.000394

Gnomad4 SAS exome AF: 0.000126

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000342

Gnomad4 OTH exome AF: 0.00331

GnomAD4 genome AF: 0.0141 AC: 2060 AN: 146104 Hom.: 49 Cov.: 30 AF XY: 0.0139 AC XY: 998 AN XY: 71548

Gnomad4 AFR AF: 0.0474

Gnomad4 AMR AF: 0.00755

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000395

Gnomad4 SAS AF: 0.000446

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000200

Gnomad4 OTH AF: 0.0124

Alfa AF: 0.000954 Hom.: 2

Bravo AF: 0.0154

Asia WGS AF: 0.00289 AC: 10 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

May 22, 2021

- -

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	-0.56
CADD	Benign	7.7
DANN	Benign	0.91

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs72645137; hg19: chr12-6484771;