chr12-6374806-G-A

Variant names:

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

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001159576.2(SCNN1A):​c.155C>T​(p.Pro52Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,726 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/18 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: SCNN1A NM_001159576.2 missense
• Clinical Significance: Not reported in ClinVar
• 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 Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.090865314).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SCNN1A	NM_001038.6	c.-23C>T		5_prime_UTR_variant	Exon 2 of 13	ENST00000228916.7	NP_001029.1
SCNN1A	NM_001159576.2	c.155C>T	p.Pro52Leu	missense_variant	Exon 1 of 12		NP_001153048.1
SCNN1A	NM_001159575.2	c.47C>T	p.Pro16Leu	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>T		5_prime_UTR_variant	Exon 2 of 13	1	NM_001038.6	ENSP00000228916.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251320 Hom.: 0 AF XY: 0.00000736 AC XY: 1 AN XY: 135882

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461726 Hom.: 0 Cov.: 32 AF XY: 0.00000413 AC XY: 3 AN XY: 727156

Gnomad4 AFR exome AF: 0.0000598

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Benign	-0.43
CADD	Benign	4.9
DANN	Benign	0.84
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.0063	N
LIST_S2	Benign	0.62	T;T;T
M_CAP	Benign	0.010	T
MetaRNN	Benign	0.091	T;T;T
MetaSVM	Benign	-0.70	T
PrimateAI	Benign	0.27	T
PROVEAN	Benign	-0.87	N;N;N
REVEL	Benign	0.15
Sift	Uncertain	0.0090	D;D;D
Sift4G	Uncertain	0.010	D;D;.
Polyphen		0.0	B;.;.
Vest4		0.089
MutPred		0.19		Loss of loop (P = 0.0288);.;.;
MVP		0.67
MPC		0.12
ClinPred		0.14	T
GERP RS		0.16
gMVP		0.32

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;