chr12-6355415-C-T

Position:

chr12-6355415-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The ENST00000228916.7(SCNN1A):c.1000G>A(p.Ala334Thr) variant causes a missense change. The variant allele was found at a frequency of 0.0643 in 1,613,752 control chromosomes in the GnomAD database, including 10,382 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Uncertain significancein ClinVar.

Frequency

Genomes: 𝑓 0.16 ( 4579 hom., cov: 32)

Exomes 𝑓: 0.054 ( 5803 hom. )

Consequence

SCNN1A
ENST00000228916.7 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: 4.32

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 links:

LOC107984500 (HGNC:):

LOC107984500 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0010077357).

BP6

Variant 12-6355415-C-T is Benign according to our data. Variant chr12-6355415-C-T is described in ClinVar as [Benign]. Clinvar id is 165165.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-6355415-C-T is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.45 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
SCNN1A	NM_001038.6 linkuse as main transcript	c.1000G>A	p.Ala334Thr	missense_variant	6/13	ENST00000228916.7	NP_001029.1
LOC107984500	XR_007063191.1 linkuse as main transcript	n.297-110C>T		intron_variant, non_coding_transcript_variant
SCNN1A	NM_001159576.2 linkuse as main transcript	c.1177G>A	p.Ala393Thr	missense_variant	5/12		NP_001153048.1
SCNN1A	NM_001159575.2 linkuse as main transcript	c.1069G>A	p.Ala357Thr	missense_variant	6/13		NP_001153047.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SCNN1A	ENST00000228916.7 linkuse as main transcript	c.1000G>A	p.Ala334Thr	missense_variant	6/13	1	NM_001038.6	ENSP00000228916	A2	P37088-1

Frequencies

GnomAD3 genomes

AF:

0.164

AC:

24999

AN:

152128

Hom.:

4555

Cov.:

show subpopulations

Gnomad AFR

AF:

0.455

Gnomad AMI

AF:

0.00219

Gnomad AMR

AF:

0.0726

Gnomad ASJ

AF:

0.0354

Gnomad EAS

AF:

0.148

Gnomad SAS

AF:

0.0585

Gnomad FIN

AF:

0.105

Gnomad MID

AF:

0.0759

Gnomad NFE

AF:

0.0367

Gnomad OTH

AF:

0.117

GnomAD3 exomes

AF:

0.0794

AC:

19801

AN:

249434

Hom.:

2143

AF XY:

0.0714

AC XY:

9636

AN XY:

134968

show subpopulations

Gnomad AFR exome

AF:

0.458

Gnomad AMR exome

AF:

0.0307

Gnomad ASJ exome

AF:

0.0459

Gnomad EAS exome

AF:

0.140

Gnomad SAS exome

AF:

0.0496

Gnomad FIN exome

AF:

0.0999

Gnomad NFE exome

AF:

0.0388

Gnomad OTH exome

AF:

0.0554

GnomAD4 exome

AF:

0.0539

AC:

78762

AN:

1461506

Hom.:

5803

Cov.:

AF XY:

0.0525

AC XY:

38171

AN XY:

727010

show subpopulations

Gnomad4 AFR exome

AF:

0.482

Gnomad4 AMR exome

AF:

0.0357

Gnomad4 ASJ exome

AF:

0.0437

Gnomad4 EAS exome

AF:

0.146

Gnomad4 SAS exome

AF:

0.0485

Gnomad4 FIN exome

AF:

0.0974

Gnomad4 NFE exome

AF:

0.0362

Gnomad4 OTH exome

AF:

0.0677

GnomAD4 genome

AF:

0.165

AC:

25079

AN:

152246

Hom.:

4579

Cov.:

AF XY:

0.164

AC XY:

12214

AN XY:

74450

show subpopulations

Gnomad4 AFR

AF:

0.456

Gnomad4 AMR

AF:

0.0724

Gnomad4 ASJ

AF:

0.0354

Gnomad4 EAS

AF:

0.149

Gnomad4 SAS

AF:

0.0581

Gnomad4 FIN

AF:

0.105

Gnomad4 NFE

AF:

0.0366

Gnomad4 OTH

AF:

0.118

Alfa

AF:

0.0611

Hom.:

1672

Bravo

AF:

0.177

TwinsUK

AF:

0.0380

AC:

141

ALSPAC

AF:

0.0376

AC:

145

ESP6500AA

AF:

0.448

AC:

1975

ESP6500EA

AF:

0.0370

AC:

318

ExAC

AF:

0.0864

AC:

10495

Asia WGS

AF:

0.125

AC:

438

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 06, 2019	This variant is associated with the following publications: (PMID: 19462466, 27582106) -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 29, 2024	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified

Benign:2

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Feb 21, 2013	Ala393Thr in exon 5 of SCNN1A: This variant is not expected to have clinical sig nificance because it has been identified in 44.8% (1975/4406) of African America n chromosomes from a broad population by the NHLBI Exome Sequencing Project (htt p://evs.gs.washington.edu/EVS; dbSNP rs11542844). -

Bronchiectasis with or without elevated sweat chloride 2

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Pseudohypoaldosteronism, type IB1, autosomal recessive

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.048

BayesDel_addAF

Benign

-0.62

BayesDel_noAF

Benign

-0.51

CADD

Benign

DANN

Benign

0.92

DEOGEN2

Benign

0.091

.;.;T;T;.

Eigen

Benign

-0.86

Eigen_PC

Benign

-0.57

FATHMM_MKL

Benign

0.15

LIST_S2

Benign

0.46

T;T;T;T;T

MetaRNN

Benign

0.0010

T;T;T;T;T

MetaSVM

Benign

-0.92

MutationAssessor

Benign

-1.5

.;.;N;.;.

MutationTaster

Benign

1.0

P;P;P;P;P;P

PrimateAI

Uncertain

0.49

PROVEAN

Benign

1.6

N;N;N;N;N

REVEL

Benign

0.076

Sift

Benign

1.0

T;T;T;T;T

Sift4G

Benign

1.0

T;T;T;T;T

Polyphen

0.0020

B;.;B;.;.

Vest4

0.19

MPC

0.11

ClinPred

0.0044

GERP RS

3.7

Varity_R

0.11

gMVP

0.50

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over