NM_001038.6:c.978C>T

Variant names:

• chr12-6355778-G-A
• rs61731141
• NM_001038.6:c.978C>T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_001038.6(SCNN1A):​c.978C>T​(p.Asn326Asn) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00478 in 1,602,436 control chromosomes in the GnomAD database, including 112 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.015 (47 hom., cov: 32)
  • Exomes 𝑓: 0.0037 (65 hom.)
• Consequence: SCNN1A NM_001038.6 splice_region, synonymous
• Scores: Splicing: ADA: 0.0004774
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.00
• Publications: 5 publications found

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

LOC107984500 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.74).
• BP6: Variant 12-6355778-G-A is Benign according to our data. Variant chr12-6355778-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 310144.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0148 (2259/152322) while in subpopulation AFR AF = 0.0449 (1868/41568). AF 95% confidence interval is 0.0432. There are 47 homozygotes in GnomAd4. There are 1089 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 47 AR,Unknown,AD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SCNN1A	NM_001038.6	c.978C>T	p.Asn326Asn	splice_region_variant, synonymous_variant	Exon 5 of 13	ENST00000228916.7	NP_001029.1
SCNN1A	NM_001159576.2	c.1155C>T	p.Asn385Asn	splice_region_variant, synonymous_variant	Exon 4 of 12		NP_001153048.1
SCNN1A	NM_001159575.2	c.1047C>T	p.Asn349Asn	splice_region_variant, synonymous_variant	Exon 5 of 13		NP_001153047.1
LOC107984500	XR_007063191.1	n.550G>A		splice_region_variant, non_coding_transcript_exon_variant	Exon 4 of 4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SCNN1A	ENST00000228916.7	c.978C>T	p.Asn326Asn	splice_region_variant, synonymous_variant	Exon 5 of 13	1	NM_001038.6	ENSP00000228916.2

Frequencies

GnomAD3 genomes AF: 0.0148 AC: 2249 AN: 152204 Hom.: 47 Cov.: 32

Gnomad AFR AF: 0.0449

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00621

Gnomad ASJ AF: 0.0112

Gnomad EAS AF: 0.000770

Gnomad SAS AF: 0.0203

Gnomad FIN AF: 0.00113

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.00159

Gnomad OTH AF: 0.0139

GnomAD2 exomes AF: 0.00746 AC: 1875 AN: 251496 AF XY: 0.00733

Gnomad AFR exome AF: 0.0475

Gnomad AMR exome AF: 0.00278

Gnomad ASJ exome AF: 0.0130

Gnomad EAS exome AF: 0.00130

Gnomad FIN exome AF: 0.00111

Gnomad NFE exome AF: 0.00156

Gnomad OTH exome AF: 0.00570

GnomAD4 exome AF: 0.00372 AC: 5396 AN: 1450114 Hom.: 65 Cov.: 28 AF XY: 0.00410 AC XY: 2961 AN XY: 722310

African (AFR) AF: 0.0466 AC: 1546 AN: 33196

American (AMR) AF: 0.00286 AC: 128 AN: 44708

Ashkenazi Jewish (ASJ) AF: 0.0127 AC: 330 AN: 26060

East Asian (EAS) AF: 0.00121 AC: 48 AN: 39662

South Asian (SAS) AF: 0.0195 AC: 1677 AN: 86032

European-Finnish (FIN) AF: 0.00110 AC: 59 AN: 53418

Middle Eastern (MID) AF: 0.0125 AC: 72 AN: 5740

European-Non Finnish (NFE) AF: 0.00100 AC: 1106 AN: 1101310

Other (OTH) AF: 0.00717 AC: 430 AN: 59988

GnomAD4 genome AF: 0.0148 AC: 2259 AN: 152322 Hom.: 47 Cov.: 32 AF XY: 0.0146 AC XY: 1089 AN XY: 74492

African (AFR) AF: 0.0449 AC: 1868 AN: 41568

American (AMR) AF: 0.00621 AC: 95 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.0112 AC: 39 AN: 3470

East Asian (EAS) AF: 0.000771 AC: 4 AN: 5186

South Asian (SAS) AF: 0.0201 AC: 97 AN: 4828

European-Finnish (FIN) AF: 0.00113 AC: 12 AN: 10612

Middle Eastern (MID) AF: 0.0170 AC: 5 AN: 294

European-Non Finnish (NFE) AF: 0.00160 AC: 109 AN: 68030

Other (OTH) AF: 0.0142 AC: 30 AN: 2114

Alfa AF: 0.00704 Hom.: 48

Bravo AF: 0.0163

Asia WGS AF: 0.0220 AC: 76 AN: 3478

EpiCase AF: 0.00234

EpiControl AF: 0.00219

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jan 23, 2021

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 31, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Bronchiectasis with or without elevated sweat chloride 2 Benign:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

not specified Benign:1

Nov 26, 2014

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

p.Asn385Asn in exon 4 of SCNN1A: This variant is not expected to have clinical s ignificance because it has been identified in 4.7% (208/4406) of African America n chromosomes by the NHLBI Exome Sequencing Project (http://evs.gs.washington.ed u/EVS/; dbSNP rs61731141). -

Pseudohypoaldosteronism, type IB1, autosomal recessive Benign:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.74
CADD	Benign	0.25
DANN	Benign	0.68
PhyloP100		0.0
Mutation Taster		=75/25	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00048
dbscSNV1_RF	Benign	0.12
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

Other links and lift over

dbSNP: rs61731141; hg19: chr12-6464944;