12-6374806-G-C

Position:

• chr12-6374806-G-C

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4_Strong BS1_Supporting

The ENST00000228916.7(SCNN1A):​c.-23C>G variant causes a 5 prime UTR 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. 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 ENST00000228916.7 5_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• 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]

ACMG classification

Verdict is Likely_benign. Variant got -5 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.013746887).
• BS1: Variant frequency is greater than expected in population eas. gnomad4_exome 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 gnomad4_exome. There are 73 alleles in male gnomad4_exome subpopulation. Median coverage is 32. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

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

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SCNN1A	ENST00000228916.7	c.-23C>G		5_prime_UTR_variant	2/13	1	NM_001038.6	ENSP00000228916	A2

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

GnomAD3 exomes AF: 0.000183 AC: 46 AN: 251320 Hom.: 0 AF XY: 0.000206 AC XY: 28 AN XY: 135882

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 SAS exome AF: 0.000229

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

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00153

Gnomad4 EAS exome AF: 0.000554

Gnomad4 SAS exome AF: 0.000243

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000270

Gnomad4 OTH exome AF: 0.000166

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

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00115

Gnomad4 EAS AF: 0.000386

Gnomad4 SAS AF: 0.000415

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

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:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Nov 02, 2017

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. -

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
MutationTaster	Benign	1.0	N;N;N;N
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

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;