12-6356915-A-G

Variant names:

• chr12-6356915-A-G
• rs3782724
• NM_001038.6:c.876-1035T>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001159576.2(SCNN1A):​c.1053-1035T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.19 in 152,114 control chromosomes in the GnomAD database, including 5,415 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 0.19 (5415 hom., cov: 32)
• Consequence: SCNN1A NM_001159576.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.511
• Publications: 17 publications found

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]

SCNN1A Gene-Disease associations (from GenCC):

• pseudohypoaldosteronism, type IB1, autosomal recessive

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: ClinGen, Laboratory for Molecular Medicine, Orphanet, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• bronchiectasis with or without elevated sweat chloride 2

  Inheritance: Unknown, AD Classification: STRONG, MODERATE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), PanelApp Australia, Ambry Genetics
• Brugada syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Liddle syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Liddle syndrome 3

  Inheritance: Unknown, AD Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.97).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.481 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001159576.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SCNN1A	NM_001038.6	MANE Select	c.876-1035T>C		intron	N/A	NP_001029.1
	SCNN1A	NM_001159576.2		c.1053-1035T>C		intron	N/A	NP_001153048.1
	SCNN1A	NM_001159575.2		c.945-1035T>C		intron	N/A	NP_001153047.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SCNN1A	ENST00000228916.7	TSL:1 MANE Select	c.876-1035T>C		intron	N/A	ENSP00000228916.2
	SCNN1A	ENST00000360168.7	TSL:1	c.1053-1035T>C		intron	N/A	ENSP00000353292.3
	SCNN1A	ENST00000540037.5	TSL:1	c.-25-1035T>C		intron	N/A	ENSP00000440876.1

Frequencies

GnomAD3 genomes AF: 0.189 AC: 28783 AN: 151996 Hom.: 5386 Cov.: 32

Gnomad AFR AF: 0.486

Gnomad AMI AF: 0.0132

Gnomad AMR AF: 0.0895

Gnomad ASJ AF: 0.0458

Gnomad EAS AF: 0.216

Gnomad SAS AF: 0.181

Gnomad FIN AF: 0.135

Gnomad MID AF: 0.111

Gnomad NFE AF: 0.0499

Gnomad OTH AF: 0.153

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

GnomAD4 genome AF: 0.190 AC: 28863 AN: 152114 Hom.: 5415 Cov.: 32 AF XY: 0.191 AC XY: 14206 AN XY: 74354

African (AFR) AF: 0.487 AC: 20162 AN: 41438

American (AMR) AF: 0.0893 AC: 1365 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.0458 AC: 159 AN: 3470

East Asian (EAS) AF: 0.216 AC: 1118 AN: 5178

South Asian (SAS) AF: 0.180 AC: 870 AN: 4824

European-Finnish (FIN) AF: 0.135 AC: 1426 AN: 10590

Middle Eastern (MID) AF: 0.112 AC: 33 AN: 294

European-Non Finnish (NFE) AF: 0.0499 AC: 3393 AN: 68016

Other (OTH) AF: 0.154 AC: 325 AN: 2106

Alfa AF: 0.116 Hom.: 5107

Bravo AF: 0.200

Asia WGS AF: 0.222 AC: 772 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.97
CADD	Benign	5.0
DANN	Benign	0.46
PhyloP100		0.51
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs3782724; hg19: chr12-6466081;