NM_001159575.2:c.16-768G>A

Variant names:

• chr12-6375605-C-T
• rs72645137
• NM_001159575.2:c.16-768G>A

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 3 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]

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

Our verdict: Benign. The variant received -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 VariationId 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 the male GnomAd4 subpopulation. Median coverage is 30. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 49 AR,Unknown,AD gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001159575.2. 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_001159575.2		c.16-768G>A		intron	N/A	NP_001153047.1	P37088-6
	LTBR	NM_001270987.2		c.39+11C>T		intron	N/A	NP_001257916.1	P36941-2
	LTBR	NM_001414309.1		c.39+11C>T		intron	N/A	NP_001401238.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SCNN1A	ENST00000543768.1	TSL:2	c.16-768G>A		intron	N/A	ENSP00000438739.1	P37088-6
	SCNN1A	ENST00000868221.1		c.-54-768G>A		intron	N/A	ENSP00000538280.1
	SCNN1A	ENST00000868222.1		c.-54-768G>A		intron	N/A	ENSP00000538281.1

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

GnomAD2 exomes AF: 0.00265 AC: 259 AN: 97890 AF XY: 0.00210

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 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

African (AFR) AF: 0.0475 AC: 1417 AN: 29846

American (AMR) AF: 0.00330 AC: 100 AN: 30316

Ashkenazi Jewish (ASJ) AF: 0.0000441 AC: 1 AN: 22670

East Asian (EAS) AF: 0.000394 AC: 13 AN: 32958

South Asian (SAS) AF: 0.000126 AC: 9 AN: 71364

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 31906

Middle Eastern (MID) AF: 0.00183 AC: 10 AN: 5454

European-Non Finnish (NFE) AF: 0.000342 AC: 358 AN: 1048044

Other (OTH) AF: 0.00331 AC: 183 AN: 55242

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

African (AFR) AF: 0.0474 AC: 1904 AN: 40194

American (AMR) AF: 0.00755 AC: 112 AN: 14828

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3302

East Asian (EAS) AF: 0.000395 AC: 2 AN: 5064

South Asian (SAS) AF: 0.000446 AC: 2 AN: 4488

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10218

Middle Eastern (MID) AF: 0.00685 AC: 2 AN: 292

European-Non Finnish (NFE) AF: 0.000200 AC: 13 AN: 64856

Other (OTH) AF: 0.0124 AC: 25 AN: 2010

Alfa AF: 0.000954 Hom.: 2

Bravo AF: 0.0154

Asia WGS AF: 0.00289 AC: 10 AN: 3478

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Bronchiectasis with or without elevated sweat chloride 1 (1)
-	-	1	not provided (1)
-	-	1	Pseudohypoaldosteronism, type IB1, autosomal recessive (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.56
CADD	Benign	7.7
DANN	Benign	0.91
PhyloP100		-0.37
PromoterAI		0.027	Neutral
Mutation Taster		=98/2	polymorphism

Splicing

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

Other links and lift over

dbSNP: rs72645137; hg19: chr12-6484771;