12-6347896-T-G

Position:

• chr12-6347896-T-G

Variant summary

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

The NM_001038.6(SCNN1A):​c.1987A>C​(p.Thr663Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000692 in 1,446,052 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T663A) has been classified as Benign.

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: SCNN1A NM_001038.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.388

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=0.07341018).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SCNN1A	NM_001038.6	c.1987A>C	p.Thr663Pro	missense_variant	13/13	ENST00000228916.7	NP_001029.1
SCNN1A	NM_001159576.2	c.2164A>C	p.Thr722Pro	missense_variant	12/12		NP_001153048.1
SCNN1A	NM_001159575.2	c.2056A>C	p.Thr686Pro	missense_variant	13/13		NP_001153047.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SCNN1A	ENST00000228916.7	c.1987A>C	p.Thr663Pro	missense_variant	13/13	1	NM_001038.6	ENSP00000228916.2

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome AF: 6.92e-7 AC: 1 AN: 1446052 Hom.: 0 Cov.: 41 AF XY: 0.00000139 AC XY: 1 AN XY: 718098

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000119

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 34

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.049
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Benign	-0.50
CADD	Benign	10
DANN	Benign	0.46
DEOGEN2	Benign	0.15	.;.;T;.
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.0093	N
LIST_S2	Benign	0.26	T;T;T;T
M_CAP	Benign	0.029	D
MetaRNN	Benign	0.073	T;T;T;T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	0.34	.;.;N;.
PrimateAI	Benign	0.45	T
PROVEAN	Benign	-0.73	N;N;N;N
REVEL	Benign	0.22
Sift	Uncertain	0.016	D;D;D;D
Sift4G	Uncertain	0.041	D;D;D;D
Polyphen		0.0	B;.;B;.
Vest4		0.078
MutPred		0.13		.;.;Loss of phosphorylation at T663 (P = 0.0353);.;
MVP		0.52
MPC		0.16
ClinPred		0.041	T
GERP RS		1.9
Varity_R		0.11
gMVP		0.23

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: rs2228576; hg19: chr12-6457062;