chr12-6375636-G-A

Variant names:

• chr12-6375636-G-A
• rs72645139
• NM_001159575.2:c.16-799C>T

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

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
• Publications: 0 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 -14 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 VariationId 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 the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 5 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.16-799C>T		intron	N/A	NP_001153047.1	P37088-6
	LTBR	NM_001270987.2		c.39+42G>A		intron	N/A	NP_001257916.1	P36941-2
	LTBR	NM_001414309.1		c.39+42G>A		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.16-799C>T		intron	N/A	ENSP00000438739.1	P37088-6
	SCNN1A	ENST00000868221.1		c.-54-799C>T		intron	N/A	ENSP00000538280.1
	SCNN1A	ENST00000868222.1		c.-54-799C>T		intron	N/A	ENSP00000538281.1

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

GnomAD2 exomes AF: 0.00213 AC: 198 AN: 93108 AF XY: 0.00209

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 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

African (AFR) AF: 0.000611 AC: 18 AN: 29442

American (AMR) AF: 0.00400 AC: 120 AN: 29966

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 22592

East Asian (EAS) AF: 0.00 AC: 0 AN: 33662

South Asian (SAS) AF: 0.000121 AC: 9 AN: 74246

European-Finnish (FIN) AF: 0.000280 AC: 9 AN: 32198

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5494

European-Non Finnish (NFE) AF: 0.00306 AC: 3228 AN: 1053740

Other (OTH) AF: 0.00161 AC: 90 AN: 55770

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

African (AFR) AF: 0.000915 AC: 38 AN: 41544

American (AMR) AF: 0.00889 AC: 136 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5176

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10608

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00293 AC: 199 AN: 68024

Other (OTH) AF: 0.00189 AC: 4 AN: 2114

Alfa AF: 0.00179 Hom.: 0

Bravo AF: 0.00273

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	Bronchiectasis with or without elevated sweat chloride 1 (1)
-	-	1	Pseudohypoaldosteronism, type IB1, autosomal recessive (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	9.4
DANN	Benign	0.77
PhyloP100		0.41
PromoterAI		0.0050	Neutral
Mutation Taster		=100/0	polymorphism

Splicing

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

Other links and lift over

dbSNP: rs72645139; hg19: chr12-6484802;