Genetic Variant NM_001038.6:c.*70T>C (chr12-6347803-A-G) – 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.*70T>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00202 in 1,375,108 control chromosomes in the GnomAD database, including 19 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0070 ( 3 hom., cov: 32)

Exomes 𝑓: 0.0014 ( 16 hom. )

Consequence

SCNN1A
NM_001038.6 3_prime_UTR

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: -1.13

Publications

0 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: Labcorp Genetics (formerly Invitae), Ambry Genetics, Orphanet, PanelApp Australia, ClinGen, Laboratory for Molecular Medicine
bronchiectasis with or without elevated sweat chloride 2
Inheritance: Unknown, AD Classification: 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:

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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=-0.88).

BP6

Variant 12-6347803-A-G is Benign according to our data. Variant chr12-6347803-A-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 310129.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 = 0.00697 (1061/152280) while in subpopulation AFR AF = 0.0218 (907/41556). AF 95% confidence interval is 0.0206. There are 3 homozygotes in GnomAd4. There are 504 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 3 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.*70T>C	3_prime_UTR	Exon 13 of 13	NP_001029.1	P37088-1
SCNN1A	NM_001159576.2		c.*70T>C	3_prime_UTR	Exon 12 of 12	NP_001153048.1	P37088-2
SCNN1A	NM_001159575.2		c.*70T>C	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.*70T>C	3_prime_UTR	Exon 13 of 13	ENSP00000228916.2	P37088-1
SCNN1A	ENST00000360168.7	TSL:1	c.*70T>C	3_prime_UTR	Exon 12 of 12	ENSP00000353292.3	P37088-2
SCNN1A	ENST00000540037.5	TSL:1	c.*70T>C	3_prime_UTR	Exon 11 of 11	ENSP00000440876.1	F5GXE6

Frequencies

GnomAD3 genomes

AF:

0.00695

AC:

1058

AN:

152162

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0218

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00393

Gnomad ASJ

AF:

0.00115

Gnomad EAS

AF:

0.00655

Gnomad SAS

AF:

0.00166

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.000441

Gnomad OTH

AF:

0.00813

GnomAD4 exome

AF:

0.00140

AC:

1714

AN:

1222828

Hom.:

Cov.:

AF XY:

0.00131

AC XY:

803

AN XY:

613788

show subpopulations

African (AFR)

AF:

0.0253

AC:

718

AN:

28392

American (AMR)

AF:

0.00300

AC:

116

AN:

38604

Ashkenazi Jewish (ASJ)

AF:

0.00253

AC:

AN:

24074

East Asian (EAS)

AF:

0.00575

AC:

214

AN:

37234

South Asian (SAS)

AF:

0.00130

AC:

100

AN:

77148

European-Finnish (FIN)

AF:

0.00

AC:

AN:

48946

Middle Eastern (MID)

AF:

0.00268

AC:

AN:

3730

European-Non Finnish (NFE)

AF:

0.000385

AC:

351

AN:

912476

Other (OTH)

AF:

0.00276

AC:

144

AN:

52224

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.494

Heterozygous variant carriers

165

248

330

413

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

128

160

<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:

0.00697

AC:

1061

AN:

152280

Hom.:

Cov.:

AF XY:

0.00677

AC XY:

504

AN XY:

74434

show subpopulations

African (AFR)

AF:

0.0218

AC:

907

AN:

41556

American (AMR)

AF:

0.00392

AC:

AN:

15304

Ashkenazi Jewish (ASJ)

AF:

0.00115

AC:

AN:

3472

East Asian (EAS)

AF:

0.00657

AC:

AN:

5178

South Asian (SAS)

AF:

0.00166

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10614

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000441

AC:

AN:

68010

Other (OTH)

AF:

0.00804

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

104

156

208

260

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<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:

0.00602

Hom.:

Bravo

AF:

0.00828

Asia WGS

AF:

0.0100

AC:

AN:

3478

ClinVar

ClinVar submissions

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Bronchiectasis with or without elevated sweat chloride 2 (1)

not provided (1)

Pseudohypoaldosteronism, type IB1, autosomal recessive (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.88

CADD

Benign

0.36

(source)

DANN

Benign

0.54

PhyloP100

-1.1

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