Genetic Variant SCNN1A:c.*633G>T (chr12-6347240-C-A) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_001038.6(SCNN1A):c.*633G>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.018 in 154,644 control chromosomes in the GnomAD database, including 30 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.018 ( 28 hom., cov: 32)

Exomes 𝑓: 0.022 ( 2 hom. )

Consequence

SCNN1A
NM_001038.6 3_prime_UTR

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: -0.447

Publications

1 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, Labcorp Genetics (formerly Invitae), Ambry Genetics, Orphanet, Laboratory for Molecular Medicine
bronchiectasis with or without elevated sweat chloride 2
Inheritance: AD, Unknown Classification: STRONG, MODERATE, LIMITED Submitted by: Ambry Genetics, PanelApp Australia, Labcorp Genetics (formerly Invitae)
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:

LOC112268088 (HGNC:):

LOC112268088 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 (BayesDel_noAF=-0.84).

BP6

Variant 12-6347240-C-A is Benign according to our data. Variant chr12-6347240-C-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 310122.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0179 (2725/152284) while in subpopulation NFE AF = 0.029 (1975/68018). AF 95% confidence interval is 0.028. There are 28 homozygotes in GnomAd4. There are 1227 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 28 AR,Unknown,AD gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001038.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
SCNN1A	NM_001038.6	MANE Select	c.*633G>T	3_prime_UTR	Exon 13 of 13	NP_001029.1	P37088-1
SCNN1A	NM_001159576.2		c.*633G>T	3_prime_UTR	Exon 12 of 12	NP_001153048.1	P37088-2
SCNN1A	NM_001159575.2		c.*633G>T	3_prime_UTR	Exon 13 of 13	NP_001153047.1	P37088-6

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
SCNN1A	ENST00000228916.7	TSL:1 MANE Select	c.*633G>T	3_prime_UTR	Exon 13 of 13	ENSP00000228916.2	P37088-1
SCNN1A	ENST00000360168.7	TSL:1	c.*633G>T	3_prime_UTR	Exon 12 of 12	ENSP00000353292.3	P37088-2
SCNN1A	ENST00000540037.5	TSL:1	c.*633G>T	3_prime_UTR	Exon 11 of 11	ENSP00000440876.1	F5GXE6

Frequencies

GnomAD3 genomes

AF:

0.0179

AC:

2724

AN:

152166

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00574

Gnomad AMI

AF:

0.00220

Gnomad AMR

AF:

0.0120

Gnomad ASJ

AF:

0.00605

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.0205

Gnomad FIN

AF:

0.0151

Gnomad MID

AF:

0.0127

Gnomad NFE

AF:

0.0290

Gnomad OTH

AF:

0.0196

GnomAD4 exome

AF:

0.0220

AC:

AN:

2360

Hom.:

Cov.:

AF XY:

0.0191

AC XY:

AN XY:

1306

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

American (AMR)

AF:

0.00830

AC:

AN:

482

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

East Asian (EAS)

AF:

0.00

AC:

AN:

South Asian (SAS)

AF:

0.0120

AC:

AN:

250

European-Finnish (FIN)

AF:

0.0714

AC:

AN:

Middle Eastern (MID)

AF:

0.00

AC:

AN:

European-Non Finnish (NFE)

AF:

0.0266

AC:

AN:

1506

Other (OTH)

AF:

0.0556

AC:

AN:

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.496

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:

0.0179

AC:

2725

AN:

152284

Hom.:

Cov.:

AF XY:

0.0165

AC XY:

1227

AN XY:

74474

show subpopulations

African (AFR)

AF:

0.00573

AC:

238

AN:

41558

American (AMR)

AF:

0.0120

AC:

184

AN:

15300

Ashkenazi Jewish (ASJ)

AF:

0.00605

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5182

South Asian (SAS)

AF:

0.0207

AC:

100

AN:

4822

European-Finnish (FIN)

AF:

0.0151

AC:

160

AN:

10620

Middle Eastern (MID)

AF:

0.0136

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0290

AC:

1975

AN:

68018

Other (OTH)

AF:

0.0194

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.496

Heterozygous variant carriers

139

278

417

556

695

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

108

144

180

<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:

0.00582

Hom.:

Bravo

AF:

0.0174

Asia WGS

AF:

0.00520

AC:

AN:

3478

ClinVar

ClinVar submissions as Germline

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

Bronchiectasis with or without elevated sweat chloride 2 (1)

Pseudohypoaldosteronism, type IB1, autosomal recessive (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.84

CADD

Benign

0.66

(source)

DANN

Benign

0.57

PhyloP100

-0.45

Mutation Taster

=100/0

polymorphism

(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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over