rs146177203

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP6BS1BS2

The NM_001038.6(SCNN1A):​c.997C>T​(p.Arg333Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0001 in 1,613,924 control chromosomes in the GnomAD database, including 3 homozygotes. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00012 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000098 ( 3 hom. )

Consequence

SCNN1A
NM_001038.6 missense

Scores

6
12
1

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:1

Conservation

PhyloP100: 7.35
Variant links:
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -9 ACMG points.

BP6
Variant 12-6355418-G-A is Benign according to our data. Variant chr12-6355418-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 229237.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=2, Benign=1}.
BS1
Variant frequency is greater than expected in population sas. gnomad4_exome allele frequency = 0.0000978 (143/1461558) while in subpopulation SAS AF= 0.000603 (52/86194). AF 95% confidence interval is 0.000472. There are 3 homozygotes in gnomad4_exome. There are 76 alleles in male gnomad4_exome subpopulation. Median coverage is 33. This position pass quality control queck.
BS2
High Homozygotes in GnomAdExome4 at 3 AD,AR gene

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
SCNN1ANM_001038.6 linkc.997C>T p.Arg333Cys missense_variant Exon 6 of 13 ENST00000228916.7 NP_001029.1 P37088-1
SCNN1ANM_001159576.2 linkc.1174C>T p.Arg392Cys missense_variant Exon 5 of 12 NP_001153048.1 P37088-2
SCNN1ANM_001159575.2 linkc.1066C>T p.Arg356Cys missense_variant Exon 6 of 13 NP_001153047.1 P37088-6
LOC107984500XR_007063191.1 linkn.297-107G>A intron_variant Intron 3 of 3

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
SCNN1AENST00000228916.7 linkc.997C>T p.Arg333Cys missense_variant Exon 6 of 13 1 NM_001038.6 ENSP00000228916.2 P37088-1

Frequencies

GnomAD3 genomes
AF:
0.000125
AC:
19
AN:
152248
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.000193
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.000827
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.000103
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.000160
AC:
40
AN:
249516
Hom.:
3
AF XY:
0.000178
AC XY:
24
AN XY:
135012
show subpopulations
Gnomad AFR exome
AF:
0.000124
Gnomad AMR exome
AF:
0.0000580
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.000984
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000356
Gnomad OTH exome
AF:
0.000327
GnomAD4 exome
AF:
0.0000978
AC:
143
AN:
1461558
Hom.:
3
Cov.:
33
AF XY:
0.000105
AC XY:
76
AN XY:
727034
show subpopulations
Gnomad4 AFR exome
AF:
0.000209
Gnomad4 AMR exome
AF:
0.0000447
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.0000756
Gnomad4 SAS exome
AF:
0.000603
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000594
Gnomad4 OTH exome
AF:
0.000182
GnomAD4 genome
AF:
0.000125
AC:
19
AN:
152366
Hom.:
0
Cov.:
32
AF XY:
0.000174
AC XY:
13
AN XY:
74510
show subpopulations
Gnomad4 AFR
AF:
0.000192
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.000828
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.000103
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.000168
Hom.:
0
Bravo
AF:
0.0000642
ESP6500AA
AF:
0.000227
AC:
1
ESP6500EA
AF:
0.00
AC:
0
ExAC
AF:
0.000189
AC:
23
Asia WGS
AF:
0.000577
AC:
2
AN:
3478
EpiCase
AF:
0.000109
EpiControl
AF:
0.00

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:2Benign:1
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

not specified Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingLaboratory for Molecular Medicine, Mass General Brigham Personalized MedicineFeb 07, 2018proposed classification - variant undergoing re-assessment, contact laboratory -
Bronchiectasis with or without elevated sweat chloride 2;C4748292:Liddle syndrome 3;C5774176:Pseudohypoaldosteronism, type IB1, autosomal recessive Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingFulgent Genetics, Fulgent GeneticsNov 03, 2021- -
not provided Benign:1
Benign, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpApr 15, 2024- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
0.50
BayesDel_addAF
Uncertain
0.077
D
BayesDel_noAF
Pathogenic
0.18
CADD
Pathogenic
34
DANN
Pathogenic
1.0
DEOGEN2
Uncertain
0.53
.;.;D;T;.
Eigen
Pathogenic
0.82
Eigen_PC
Pathogenic
0.74
FATHMM_MKL
Uncertain
0.88
D
LIST_S2
Uncertain
0.96
D;D;D;D;D
M_CAP
Uncertain
0.10
D
MetaRNN
Uncertain
0.43
T;T;T;T;T
MetaSVM
Uncertain
0.013
D
MutationAssessor
Uncertain
2.7
.;.;M;.;.
PrimateAI
Uncertain
0.60
T
PROVEAN
Pathogenic
-6.3
D;D;D;D;D
REVEL
Uncertain
0.62
Sift
Uncertain
0.014
D;D;D;D;D
Sift4G
Pathogenic
0.0010
D;D;D;D;D
Polyphen
1.0
D;.;D;.;.
Vest4
0.93
MVP
0.90
MPC
0.66
ClinPred
0.39
T
GERP RS
3.9
Varity_R
0.59
gMVP
0.80

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.050
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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs146177203; hg19: chr12-6464584; API