Genetic Variant NM_001038.6:c.417-3847G>A (chr12-6367557-C-T) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_001038.6(SCNN1A):c.417-3847G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.409 in 151,978 control chromosomes in the GnomAD database, including 12,927 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.41 ( 12927 hom., cov: 32)

Consequence

SCNN1A
NM_001038.6 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.989

Publications

6 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:

LOC105369626 (HGNC:):

LOC105369626 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.99).

BA1

GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.515 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein	UniProt
SCNN1A	NM_001038.6 link	c.417-3847G>A	intron_variant	Intron 2 of 12	ENST00000228916.7	NP_001029.1	P37088-1
SCNN1A	NM_001159576.2 link	c.594-3847G>A	intron_variant	Intron 1 of 11		NP_001153048.1	P37088-2
SCNN1A	NM_001159575.2 link	c.486-3847G>A	intron_variant	Intron 2 of 12		NP_001153047.1	P37088-6
LOC105369626	XR_931591.3 link	n.470-1058C>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.417-3847G>A		intron_variant	Intron 2 of 12	1	NM_001038.6	ENSP00000228916.2		P37088-1

Frequencies

GnomAD3 genomes

AF:

0.409

AC:

62133

AN:

151860

Hom.:

12922

Cov.:

show subpopulations

Gnomad AFR

AF:

0.374

Gnomad AMI

AF:

0.413

Gnomad AMR

AF:

0.524

Gnomad ASJ

AF:

0.455

Gnomad EAS

AF:

0.471

Gnomad SAS

AF:

0.352

Gnomad FIN

AF:

0.349

Gnomad MID

AF:

0.424

Gnomad NFE

AF:

0.410

Gnomad OTH

AF:

0.444

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome

AF:

0.409

AC:

62174

AN:

151978

Hom.:

12927

Cov.:

AF XY:

0.409

AC XY:

30349

AN XY:

74264

show subpopulations

African (AFR)

AF:

0.373

AC:

15472

AN:

41432

American (AMR)

AF:

0.525

AC:

8005

AN:

15260

Ashkenazi Jewish (ASJ)

AF:

0.455

AC:

1577

AN:

3468

East Asian (EAS)

AF:

0.471

AC:

2439

AN:

5178

South Asian (SAS)

AF:

0.353

AC:

1699

AN:

4818

European-Finnish (FIN)

AF:

0.349

AC:

3678

AN:

10532

Middle Eastern (MID)

AF:

0.412

AC:

121

AN:

294

European-Non Finnish (NFE)

AF:

0.410

AC:

27872

AN:

67976

Other (OTH)

AF:

0.443

AC:

935

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

1904

3807

5711

7614

9518

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

592

1184

1776

2368

2960

<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:

0.415

Hom.:

52873

Bravo

AF:

0.421

Asia WGS

AF:

0.393

AC:

1365

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.99

CADD

Benign

0.76

(source)

DANN

Benign

0.56

PhyloP100

-0.99

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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over