chr12-6349339-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_StrongBP6BS1

The NM_001038.6(SCNN1A):c.1427G>A(p.Arg476Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000231 in 1,613,034 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R476W) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0011 ( 0 hom., cov: 30)

Exomes 𝑓: 0.00014 ( 1 hom. )

Consequence

SCNN1A
NM_001038.6 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 1.32

Publications

4 publications found

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]

SCNN1A Gene-Disease associations (from GenCC):

pseudohypoaldosteronism, type IB1, autosomal recessive
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: ClinGen, Laboratory for Molecular Medicine, Orphanet, Ambry Genetics, Labcorp Genetics (formerly Invitae)
bronchiectasis with or without elevated sweat chloride 2
Inheritance: Unknown, AD Classification: STRONG, MODERATE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), PanelApp Australia, Ambry Genetics
Brugada syndrome
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
Liddle syndrome
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
Liddle syndrome 3
Inheritance: Unknown, AD Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics

SCNN1A links:

LOC107984500 (HGNC:):

LOC107984500 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.012654841).

BP6

Variant 12-6349339-C-T is Benign according to our data. Variant chr12-6349339-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 598965.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00114 (174/152204) while in subpopulation AFR AF = 0.004 (166/41510). AF 95% confidence interval is 0.0035. There are 0 homozygotes in GnomAd4. There are 82 alleles in the male GnomAd4 subpopulation. Median coverage is 30. This position passed quality control check.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SCNN1A	NM_001038.6 link	c.1427G>A	p.Arg476Gln	missense_variant	Exon 9 of 13	ENST00000228916.7	NP_001029.1	P37088-1
SCNN1A	NM_001159576.2 link	c.1604G>A	p.Arg535Gln	missense_variant	Exon 8 of 12		NP_001153048.1	P37088-2
SCNN1A	NM_001159575.2 link	c.1496G>A	p.Arg499Gln	missense_variant	Exon 9 of 13		NP_001153047.1	P37088-6
LOC107984500	XR_007063191.1 link	n.87+1072C>T		intron_variant	Intron 1 of 3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SCNN1A	ENST00000228916.7 link	c.1427G>A	p.Arg476Gln	missense_variant	Exon 9 of 13	1	NM_001038.6	ENSP00000228916.2		P37088-1

Frequencies

GnomAD3 genomes

AF:

0.00115

AC:

175

AN:

152086

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00403

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000196

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000588

Gnomad OTH

AF:

0.000478

GnomAD2 exomes

AF:

0.000322

AC:

AN:

248698

AF XY:

0.000230

show subpopulations

Gnomad AFR exome

AF:

0.00451

Gnomad AMR exome

AF:

0.0000584

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000534

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000136

AC:

198

AN:

1460830

Hom.:

Cov.:

AF XY:

0.000107

AC XY:

AN XY:

726660

show subpopulations

African (AFR)

AF:

0.00416

AC:

139

AN:

33448

American (AMR)

AF:

0.0000449

AC:

AN:

44536

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26122

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39642

South Asian (SAS)

AF:

0.0000348

AC:

AN:

86120

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53362

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.0000396

AC:

AN:

1111484

Other (OTH)

AF:

0.000149

AC:

AN:

60350

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.466

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00114

AC:

174

AN:

152204

Hom.:

Cov.:

AF XY:

0.00110

AC XY:

AN XY:

74416

show subpopulations

African (AFR)

AF:

0.00400

AC:

166

AN:

41510

American (AMR)

AF:

0.000196

AC:

AN:

15294

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5184

South Asian (SAS)

AF:

0.00

AC:

AN:

4814

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10604

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000588

AC:

AN:

68006

Other (OTH)

AF:

0.000473

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000485

Hom.:

Bravo

AF:

0.00120

ESP6500AA

AF:

0.00272

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000437

AC:

Asia WGS

AF:

0.000577

AC:

AN:

3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:2Benign:1

Jan 23, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Nov 19, 2018

Center for Personalized Medicine, Children's Hospital Los Angeles

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.10

BayesDel_addAF

Benign

-0.35

BayesDel_noAF

Benign

-0.27

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.17

.;.;T;T;.

Eigen

Benign

0.095

Eigen_PC

Benign

0.18

FATHMM_MKL

Uncertain

0.80

LIST_S2

Uncertain

0.93

D;D;D;D;D

M_CAP

Benign

0.065

MetaRNN

Benign

0.013

T;T;T;T;T

MetaSVM

Benign

-0.78

MutationAssessor

Uncertain

2.1

.;.;M;.;.

PhyloP100

1.3

PrimateAI

Uncertain

0.49

PROVEAN

Benign

-1.8

N;N;N;N;N

REVEL

Benign

0.19

Sift

Benign

0.11

T;T;T;T;T

Sift4G

Benign

0.29

T;T;T;T;T

Polyphen

0.33

B;.;P;.;.

Vest4

0.53

MVP

0.75

MPC

0.46

ClinPred

0.059

GERP RS

4.5

Varity_R

0.25

gMVP

0.56

Mutation Taster

=73/27

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over