12-6377358-T-C

Position:

• chr12-6377358-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001159575.2(SCNN1A):​c.-92A>G variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00545 in 1,175,254 control chromosomes in the GnomAD database, including 239 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.025 (152 hom., cov: 33)
  • Exomes 𝑓: 0.0025 (87 hom.)
• Consequence: SCNN1A NM_001159575.2 5_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.0760

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=-0.86).
• BP6: Variant 12-6377358-T-C is Benign according to our data. Variant chr12-6377358-T-C is described in ClinVar as [Benign]. Clinvar id is 1228146.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0845 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SCNN1A	NM_001159575.2	c.-92A>G		5_prime_UTR_variant	1/13		NP_001153047.1
LTBR	NM_001270987.2	c.39+1764T>C		intron_variant			NP_001257916.1
LTBR	NM_001414309.1	c.39+1764T>C		intron_variant			NP_001401238.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SCNN1A	ENST00000543768.1	c.-92A>G		5_prime_UTR_variant	1/13	2		ENSP00000438739	P4
SCNN1A	ENST00000536788.1	c.9+309A>G		intron_variant		4		ENSP00000443434
LTBR	ENST00000539925.5	c.39+1764T>C		intron_variant		2		ENSP00000440875	A2

Frequencies

GnomAD3 genomes AF: 0.0248 AC: 3778 AN: 152174 Hom.: 151 Cov.: 33

Gnomad AFR AF: 0.0866

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00870

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000829

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000294

Gnomad OTH AF: 0.0163

GnomAD4 exome AF: 0.00255 AC: 2608 AN: 1022962 Hom.: 87 Cov.: 13 AF XY: 0.00226 AC XY: 1170 AN XY: 518270

Gnomad4 AFR exome AF: 0.0860

Gnomad4 AMR exome AF: 0.00482

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000886

Gnomad4 SAS exome AF: 0.000204

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000149

Gnomad4 OTH exome AF: 0.00673

GnomAD4 genome AF: 0.0250 AC: 3800 AN: 152292 Hom.: 152 Cov.: 33 AF XY: 0.0242 AC XY: 1801 AN XY: 74456

Gnomad4 AFR AF: 0.0869

Gnomad4 AMR AF: 0.00862

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000830

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000294

Gnomad4 OTH AF: 0.0161

Alfa AF: 0.0198 Hom.: 10

Bravo AF: 0.0281

Asia WGS AF: 0.00779 AC: 27 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 19, 2020	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	10
DANN	Benign	0.74

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs72645155; hg19: chr12-6486524;