rs149484264

chr12-6354776-G-Achr12-6354776-G-T

Variant summary

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

The NM_001038.6(SCNN1A):c.1216C>T(p.Leu406Phe) 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 1,461,830 control chromosomes in the GnomAD database, with no homozygous occurrence. 12/21 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. L406I) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: SCNN1A NM_001038.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.35

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]

LOC107984500 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SCNN1A	NM_001038.6	c.1216C>T	p.Leu406Phe	missense_variant	7/13	ENST00000228916.7
LOC107984500	XR_007063191.1	n.297-749G>A		intron_variant, non_coding_transcript_variant
SCNN1A	NM_001159576.2	c.1393C>T	p.Leu465Phe	missense_variant	6/12
SCNN1A	NM_001159575.2	c.1285C>T	p.Leu429Phe	missense_variant	7/13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SCNN1A	ENST00000228916.7	c.1216C>T	p.Leu406Phe	missense_variant	7/13	1	NM_001038.6	A2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251486 Hom.: 0 AF XY: 0.00000736 AC XY: 1 AN XY: 135918

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: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000879

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461830 Hom.: 0 Cov.: 32 AF XY: 0.00000275 AC XY: 2 AN XY: 727220

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: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000270

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000824 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.0064	T
BayesDel_noAF	Benign	-0.25
Cadd	Benign	21
Dann	Uncertain	1.0
Eigen	Uncertain	0.19
Eigen_PC	Benign	0.18
FATHMM_MKL	Uncertain	0.81	D
LIST_S2	Benign	0.80	T;T;T;T;T
M_CAP	Benign	0.038	D
MetaRNN	Uncertain	0.47	T;T;T;T;T
MetaSVM	Benign	-0.57	T
MutationTaster	Benign	1.0	D;D;D;D;D;D
PrimateAI	Benign	0.46	T
PROVEAN	Uncertain	-3.3	D;D;D;D;D
REVEL	Benign	0.28
Sift	Benign	0.11	T;T;D;D;D
Sift4G	Uncertain	0.021	D;D;D;D;D
Polyphen		0.86	P;.;P;.;.
Vest4		0.23
MutPred		0.76		.;.;Gain of sheet (P = 0.0477);Gain of sheet (P = 0.0477);.;
MVP		0.83
MPC		0.23
ClinPred		0.89	D
GERP RS		2.1
Varity_R		0.18
gMVP		0.67

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: rs149484264; hg19: chr12-6463942;