12-6376495-T-C

Position:

• chr12-6376495-T-C

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_Moderate BA1

The NM_001159575.2(SCNN1A):​c.15+757A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.384 in 152,030 control chromosomes in the GnomAD database, including 13,683 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.38 (13683 hom., cov: 33)
• Consequence: SCNN1A NM_001159575.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0200

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=-0.4).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.629 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SCNN1A	NM_001159575.2	c.15+757A>G		intron_variant			NP_001153047.1
LTBR	NM_001270987.2	c.39+901T>C		intron_variant			NP_001257916.1
LTBR	NM_001414309.1	c.39+901T>C		intron_variant			NP_001401238.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SCNN1A	ENST00000536788.1	c.9+1172A>G		intron_variant		4		ENSP00000443434
LTBR	ENST00000539925.5	c.39+901T>C		intron_variant		2		ENSP00000440875	A2
SCNN1A	ENST00000543768.1	c.15+757A>G		intron_variant		2		ENSP00000438739	P4

Frequencies

GnomAD3 genomes AF: 0.383 AC: 58247 AN: 151912 Hom.: 13660 Cov.: 33

Gnomad AFR AF: 0.636

Gnomad AMI AF: 0.276

Gnomad AMR AF: 0.399

Gnomad ASJ AF: 0.174

Gnomad EAS AF: 0.633

Gnomad SAS AF: 0.381

Gnomad FIN AF: 0.263

Gnomad MID AF: 0.184

Gnomad NFE AF: 0.241

Gnomad OTH AF: 0.333

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.384 AC: 58327 AN: 152030 Hom.: 13683 Cov.: 33 AF XY: 0.385 AC XY: 28594 AN XY: 74304

Gnomad4 AFR AF: 0.636

Gnomad4 AMR AF: 0.400

Gnomad4 ASJ AF: 0.174

Gnomad4 EAS AF: 0.634

Gnomad4 SAS AF: 0.381

Gnomad4 FIN AF: 0.263

Gnomad4 NFE AF: 0.241

Gnomad4 OTH AF: 0.333

Alfa AF: 0.296 Hom.: 5765

Bravo AF: 0.404

Asia WGS AF: 0.508 AC: 1770 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.40
CADD	Benign	11
DANN	Benign	0.78

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs3759324; hg19: chr12-6485661;