12-6374806-G-C

Variant names:

• chr12-6374806-G-C
• rs377074479
• ENST00000360168.7:c.155C>G

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4_Strong BS1_Supporting

The NM_001159576.2(SCNN1A):​c.155C>G​(p.Pro52Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000083 in 1,614,020 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000085 (0 hom.)
• Consequence: SCNN1A NM_001159576.2 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: -0.0450

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: Likely_benign. The variant received -5 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.013746887).
• BS1: Variant frequency is greater than expected in population eas. GnomAdExome4 allele frequency = 0.0000848 (124/1461726) while in subpopulation EAS AF = 0.000554 (22/39696). AF 95% confidence interval is 0.000375. There are 0 homozygotes in GnomAdExome4. There are 73 alleles in the male GnomAdExome4 subpopulation. Median coverage is 32. This position FAILED quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SCNN1A	NM_001038.6	c.-23C>G		5_prime_UTR_variant	Exon 2 of 13	ENST00000228916.7	NP_001029.1
SCNN1A	NM_001159576.2	c.155C>G	p.Pro52Arg	missense_variant	Exon 1 of 12		NP_001153048.1
SCNN1A	NM_001159575.2	c.47C>G	p.Pro16Arg	missense_variant	Exon 2 of 13		NP_001153047.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SCNN1A	ENST00000228916.7	c.-23C>G		5_prime_UTR_variant	Exon 2 of 13	1	NM_001038.6	ENSP00000228916.2

Frequencies

GnomAD3 genomes AF: 0.0000657 AC: 10 AN: 152176 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00115

Gnomad EAS AF: 0.000385

Gnomad SAS AF: 0.000415

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000183 AC: 46 AN: 251320 AF XY: 0.000206

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00208

Gnomad EAS exome AF: 0.000381

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000792

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.0000848 AC: 124 AN: 1461726 Hom.: 0 Cov.: 32 AF XY: 0.000100 AC XY: 73 AN XY: 727156

Gnomad4 AFR exome AF: 0.00 AC: 0 AN: 33424

Gnomad4 AMR exome AF: 0.0000224 AC: 1 AN: 44714

Gnomad4 ASJ exome AF: 0.00153 AC: 40 AN: 26136

Gnomad4 EAS exome AF: 0.000554 AC: 22 AN: 39696

Gnomad4 SAS exome AF: 0.000243 AC: 21 AN: 86256

Gnomad4 FIN exome AF: 0.00 AC: 0 AN: 53370

Gnomad4 NFE exome AF: 0.0000270 AC: 30 AN: 1111982

Gnomad4 Remaining exome AF: 0.000166 AC: 10 AN: 60382

GnomAD4 genome AF: 0.0000657 AC: 10 AN: 152294 Hom.: 0 Cov.: 32 AF XY: 0.0000672 AC XY: 5 AN XY: 74458

Gnomad4 AFR AF: 0.0000241 AC: 0.0000240639 AN: 0.0000240639

Gnomad4 AMR AF: 0.00 AC: 0 AN: 0

Gnomad4 ASJ AF: 0.00115 AC: 0.00115207 AN: 0.00115207

Gnomad4 EAS AF: 0.000386 AC: 0.000385951 AN: 0.000385951

Gnomad4 SAS AF: 0.000415 AC: 0.000415282 AN: 0.000415282

Gnomad4 FIN AF: 0.00 AC: 0 AN: 0

Gnomad4 NFE AF: 0.0000147 AC: 0.0000147024 AN: 0.0000147024

Gnomad4 OTH AF: 0.00 AC: 0 AN: 0

Alfa AF: 0.000225 Hom.: 0

Bravo AF: 0.0000718

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.000231 AC: 28

EpiCase AF: 0.000109

EpiControl AF: 0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Uncertain:1

Nov 02, 2017

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant classified as Uncertain Significance - Favor Benign. The p.Pro52Arg vari ant in SCNN1A has not been reported in individuals with pulmonary disease, but h as been identified in 0.2% (22/10146) of Ashkenazi Jewish chromosomes by the Gen ome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs3770 74479). Computational prediction tools and conservation analysis suggest that th e variant may not impact the protein, though this information is not predictive enough to rule out pathogenicity. In summary, while the clinical significance of the p.Pro52Arg variant is uncertain, its frequency suggests that it is more lik ely to be benign. ACMG/AMP Criteria applied: BP4. -

Bronchiectasis with or without elevated sweat chloride 2;C4748292:Liddle syndrome 3;C5774176:Pseudohypoaldosteronism, type IB1, autosomal recessive Uncertain:1

Nov 12, 2021

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: research

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.34	T
BayesDel_noAF	Benign	-0.41
CADD	Benign	4.2
DANN	Benign	0.91
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.052	N
LIST_S2	Benign	0.50	T;T;T
M_CAP	Benign	0.010	T
MetaRNN	Benign	0.014	T;T;T
MetaSVM	Benign	-0.67	T
PrimateAI	Benign	0.26	T
PROVEAN	Benign	-0.75	N;N;N
REVEL	Benign	0.11
Sift	Uncertain	0.0060	D;D;D
Sift4G	Uncertain	0.010	D;D;.
Polyphen		0.15	B;.;.
Vest4		0.20
MVP		0.70
MPC		0.14
ClinPred		0.0092	T
GERP RS		0.16
gMVP		0.36
Mutation Taster		=95/5	polymorphism

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

Publications

LitVar

Other links and lift over

dbSNP: rs377074479; hg19: chr12-6483972;