12-6347896-T-C

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_001038.6(SCNN1A):c.1987A>G(p.Thr663Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.681 in 1,596,108 control chromosomes in the GnomAD database, including 374,537 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T663V) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.75 ( 43519 hom., cov: 34)

Exomes 𝑓: 0.67 ( 331018 hom. )

Consequence

SCNN1A
NM_001038.6 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:13

Conservation

PhyloP100: -0.388

Publications

93 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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=9.429439E-7).

BP6

Variant 12-6347896-T-C is Benign according to our data. Variant chr12-6347896-T-C is described in ClinVar as Benign. ClinVar VariationId is 165164.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.897 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
SCNN1A	NM_001038.6 link	c.1987A>G	p.Thr663Ala	missense_variant	Exon 13 of 13	ENST00000228916.7	NP_001029.1
SCNN1A	NM_001159576.2 link	c.2164A>G	p.Thr722Ala	missense_variant	Exon 12 of 12		NP_001153048.1
SCNN1A	NM_001159575.2 link	c.2056A>G	p.Thr686Ala	missense_variant	Exon 13 of 13		NP_001153047.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SCNN1A	ENST00000228916.7 link	c.1987A>G	p.Thr663Ala	missense_variant	Exon 13 of 13	1	NM_001038.6	ENSP00000228916.2

Frequencies

GnomAD3 genomes

AF:

0.747

AC:

113634

AN:

152042

Hom.:

43465

Cov.:

show subpopulations

Gnomad AFR

AF:

0.905

Gnomad AMI

AF:

0.654

Gnomad AMR

AF:

0.775

Gnomad ASJ

AF:

0.761

Gnomad EAS

AF:

0.508

Gnomad SAS

AF:

0.745

Gnomad FIN

AF:

0.706

Gnomad MID

AF:

0.761

Gnomad NFE

AF:

0.671

Gnomad OTH

AF:

0.742

GnomAD2 exomes

AF:

0.694

AC:

154065

AN:

221868

AF XY:

0.691

show subpopulations

Gnomad AFR exome

AF:

0.909

Gnomad AMR exome

AF:

0.760

Gnomad ASJ exome

AF:

0.753

Gnomad EAS exome

AF:

0.499

Gnomad FIN exome

AF:

0.696

Gnomad NFE exome

AF:

0.660

Gnomad OTH exome

AF:

0.701

GnomAD4 exome

AF:

0.674

AC:

973645

AN:

1443946

Hom.:

331018

Cov.:

AF XY:

0.676

AC XY:

484796

AN XY:

717104

show subpopulations

African (AFR)

AF:

0.917

AC:

30439

AN:

33212

American (AMR)

AF:

0.761

AC:

32694

AN:

42948

Ashkenazi Jewish (ASJ)

AF:

0.752

AC:

19415

AN:

25802

East Asian (EAS)

AF:

0.560

AC:

22053

AN:

39384

South Asian (SAS)

AF:

0.741

AC:

62408

AN:

84186

European-Finnish (FIN)

AF:

0.706

AC:

36332

AN:

51450

Middle Eastern (MID)

AF:

0.749

AC:

3544

AN:

4734

European-Non Finnish (NFE)

AF:

0.658

AC:

725887

AN:

1102578

Other (OTH)

AF:

0.685

AC:

40873

AN:

59652

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.463

Heterozygous variant carriers

15860

31720

47581

63441

79301

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

18996

37992

56988

75984

94980

<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:

0.748

AC:

113745

AN:

152162

Hom.:

43519

Cov.:

AF XY:

0.749

AC XY:

55726

AN XY:

74386

show subpopulations

African (AFR)

AF:

0.905

AC:

37600

AN:

41552

American (AMR)

AF:

0.774

AC:

11842

AN:

15294

Ashkenazi Jewish (ASJ)

AF:

0.761

AC:

2640

AN:

3470

East Asian (EAS)

AF:

0.508

AC:

2621

AN:

5158

South Asian (SAS)

AF:

0.745

AC:

3596

AN:

4826

European-Finnish (FIN)

AF:

0.706

AC:

7470

AN:

10576

Middle Eastern (MID)

AF:

0.750

AC:

219

AN:

292

European-Non Finnish (NFE)

AF:

0.671

AC:

45597

AN:

67974

Other (OTH)

AF:

0.742

AC:

1564

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.509

Heterozygous variant carriers

1471

2942

4414

5885

7356

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

844

1688

2532

3376

4220

<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:

0.689

Hom.:

54010

Bravo

AF:

0.753

TwinsUK

AF:

0.659

AC:

2443

ALSPAC

AF:

0.648

AC:

2498

ESP6500AA

AF:

0.900

AC:

3760

ESP6500EA

AF:

0.693

AC:

5675

ExAC

AF:

0.680

AC:

81091

Asia WGS

AF:

0.658

AC:

2292

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:13

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:5

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

Mar 05, 2015

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Jun 11, 2013

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Benign based on allele frequency. A single GWAS study comparing nenoates with s mall intestinal atresia to controls. The variant is reported to correlate with blood pressure (OR 0.7, 95% CI 0.4-1.3). This is insufficient to warrant inclus ion on a Mendelian report

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

not provided

Benign:3

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Sep 04, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 19462466, 10523338, 15069064, 16249274)

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

Bronchiectasis with or without elevated sweat chloride 2

Benign:2

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to rule this variant out of causing disease. Therefore, this variant is classified as benign.

Jul 15, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Pseudohypoaldosteronism, type IB1, autosomal recessive

Benign:2

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign.

Jul 15, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Liddle syndrome 3

Benign:1

Jul 15, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.050

BayesDel_addAF

Benign

-0.73

BayesDel_noAF

Benign

-0.68

CADD

Benign

0.25

(source)

DANN

Benign

0.46

DEOGEN2

Benign

0.0

.;.;T;.

Eigen

Benign

-1.6

Eigen_PC

Benign

-1.5

FATHMM_MKL

Benign

0.00050

LIST_S2

Benign

0.22

T;T;T;T

MetaRNN

Benign

9.4e-7

T;T;T;T

MetaSVM

Benign

-0.94

MutationAssessor

Benign

0.0

.;.;N;.

PhyloP100

-0.39

PrimateAI

Benign

0.44

PROVEAN

Benign

0.28

N;N;N;N

REVEL

Benign

0.14

Sift

Benign

1.0

T;T;T;T

Sift4G

Benign

1.0

T;T;T;T

Vest4

0.011

ClinPred

0.0029

GERP RS

1.9

Varity_R

0.031

gMVP

0.15

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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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