12-6375636-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.16-799C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00259 in 1,489,374 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0025 (1 hom., cov: 31)
  • Exomes 𝑓: 0.0026 (5 hom.)
• Consequence: SCNN1A NM_001159575.2 intron
• Clinical Significance: Likely benign criteria provided, single submitter B:2
• Conservation: PhyloP100: 0.405

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=-0.81).
• BP6: Variant 12-6375636-G-A is Benign according to our data. Variant chr12-6375636-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 310162.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.00248 (378/152264) while in subpopulation AMR AF= 0.00889 (136/15296). AF 95% confidence interval is 0.00767. There are 1 homozygotes in gnomad4. There are 191 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SCNN1A	NM_001159575.2	c.16-799C>T		intron_variant
LTBR	NM_001270987.2	c.39+42G>A		intron_variant
LTBR	NM_001414309.1	c.39+42G>A		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SCNN1A	ENST00000536788.1	c.10-799C>T		intron_variant		4
LTBR	ENST00000539925.5	c.39+42G>A		intron_variant		2		A2
SCNN1A	ENST00000543768.1	c.16-799C>T		intron_variant		2		P4

Frequencies

GnomAD3 genomes AF: 0.00248 AC: 378 AN: 152146 Hom.: 1 Cov.: 31

Gnomad AFR AF: 0.000917

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00890

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00293

Gnomad OTH AF: 0.00191

GnomAD3 exomes AF: 0.00213 AC: 198 AN: 93108 Hom.: 1 AF XY: 0.00209 AC XY: 106 AN XY: 50644

Gnomad AFR exome AF: 0.00106

Gnomad AMR exome AF: 0.00422

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000302

Gnomad FIN exome AF: 0.000285

Gnomad NFE exome AF: 0.00305

Gnomad OTH exome AF: 0.00170

GnomAD4 exome AF: 0.00260 AC: 3474 AN: 1337110 Hom.: 5 Cov.: 36 AF XY: 0.00251 AC XY: 1647 AN XY: 655322

Gnomad4 AFR exome AF: 0.000611

Gnomad4 AMR exome AF: 0.00400

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000121

Gnomad4 FIN exome AF: 0.000280

Gnomad4 NFE exome AF: 0.00306

Gnomad4 OTH exome AF: 0.00161

GnomAD4 genome AF: 0.00248 AC: 378 AN: 152264 Hom.: 1 Cov.: 31 AF XY: 0.00257 AC XY: 191 AN XY: 74460

Gnomad4 AFR AF: 0.000915

Gnomad4 AMR AF: 0.00889

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00293

Gnomad4 OTH AF: 0.00189

Alfa AF: 0.00179 Hom.: 0

Bravo AF: 0.00273

Asia WGS AF: 0.000577 AC: 2 AN: 3478

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	-0.81
Cadd	Benign	9.4
Dann	Benign	0.77

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs72645139; hg19: chr12-6484802;