chr12-6374831-T-C

Position:

chr12-6374831-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_001159576.2(SCNN1A):c.130A>G(p.Lys44Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00125 in 1,614,058 control chromosomes in the GnomAD database, including 18 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/17 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0066 ( 4 hom., cov: 32)

Exomes 𝑓: 0.00069 ( 14 hom. )

Consequence

SCNN1A
NM_001159576.2 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: -0.949

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:

SCNN1A (HGNC:):

SCNN1A links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0031102896).

BP6

Variant 12-6374831-T-C is Benign according to our data. Variant chr12-6374831-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 310155.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00658 (1001/152210) while in subpopulation AFR AF= 0.0223 (924/41518). AF 95% confidence interval is 0.0211. There are 4 homozygotes in gnomad4. There are 447 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 4 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SCNN1A	NM_001038.6 linkuse as main transcript	c.-48A>G		5_prime_UTR_variant	2/13	ENST00000228916.7	NP_001029.1	P37088-1
SCNN1A	NM_001159576.2 linkuse as main transcript	c.130A>G	p.Lys44Glu	missense_variant	1/12		NP_001153048.1	P37088-2
SCNN1A	NM_001159575.2 linkuse as main transcript	c.22A>G	p.Lys8Glu	missense_variant	2/13		NP_001153047.1	P37088-6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SCNN1A	ENST00000228916.7 linkuse as main transcript	c.-48A>G		5_prime_UTR_variant	2/13	1	NM_001038.6	ENSP00000228916.2		P37088-1

Frequencies

GnomAD3 genomes

AF:

0.00659

AC:

1003

AN:

152092

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0224

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00406

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:

0.0000294

Gnomad OTH

AF:

0.00623

GnomAD3 exomes

AF:

0.00177

AC:

445

AN:

251194

Hom.:

AF XY:

0.00138

AC XY:

187

AN XY:

135854

show subpopulations

Gnomad AFR exome

AF:

0.0244

Gnomad AMR exome

AF:

0.00121

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000980

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000880

Gnomad OTH exome

AF:

0.000653

GnomAD4 exome

AF:

0.000691

AC:

1010

AN:

1461848

Hom.:

Cov.:

AF XY:

0.000579

AC XY:

421

AN XY:

727224

show subpopulations

Gnomad4 AFR exome

AF:

0.0240

Gnomad4 AMR exome

AF:

0.00163

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000198

Gnomad4 OTH exome

AF:

0.00156

GnomAD4 genome

AF:

0.00658

AC:

1001

AN:

152210

Hom.:

Cov.:

AF XY:

0.00601

AC XY:

447

AN XY:

74436

show subpopulations

Gnomad4 AFR

AF:

0.0223

Gnomad4 AMR

AF:

0.00405

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000294

Gnomad4 OTH

AF:

0.00617

Alfa

AF:

0.00103

Hom.:

Bravo

AF:

0.00762

ESP6500AA

AF:

0.0254

AC:

112

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.00231

AC:

280

Asia WGS

AF:

0.000577

AC:

AN:

3478

EpiCase

AF:

0.000109

EpiControl

AF:

0.00

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 23, 2021	See Variant Classification Assertion Criteria. -

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Nov 02, 2017

p.Lys44Glu in exon 1 of SCNN1A: This variant is not expected to have clinical si gnificance because it has been identified in 2.2% (531/23990) of African America n chromosomes including 4 homozygotes by the Genome Aggregation Database (gnomAD , http://gnomad.broadinstitute.org; dbSNP rs150809388). -

Bronchiectasis with or without elevated sweat chloride 2

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 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 13, 2018

SCNN1A-related disorder

Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Apr 12, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Benign

-0.43

BayesDel_noAF

Benign

-0.37

CADD

Benign

6.7

DANN

Benign

0.97

Eigen

Benign

-1.4

Eigen_PC

Benign

-1.4

FATHMM_MKL

Benign

0.031

LIST_S2

Benign

0.36

T;T;T

MetaRNN

Benign

0.0031

T;T;T

MetaSVM

Benign

-0.83

PrimateAI

Benign

0.29

PROVEAN

Benign

-0.31

N;N;N

REVEL

Benign

0.16

Sift

Uncertain

0.026

D;D;T

Sift4G

Benign

0.084

T;T;.

Polyphen

0.0

B;.;.

Vest4

0.15

MVP

0.32

MPC

0.19

ClinPred

0.0060

GERP RS

-3.0

gMVP

0.32

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

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