rs61731141

Positions:

• chr12-6355778-G-A

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The ENST00000228916.7(SCNN1A):​c.978C>T​(p.Asn326=) 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 ENST00000228916.7 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

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]

LOC107984500 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -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 [Likely_benign]. Clinvar id 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 male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 47 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SCNN1A	NM_001038.6	c.978C>T	p.Asn326=	splice_region_variant, synonymous_variant	5/13	ENST00000228916.7	NP_001029.1
LOC107984500	XR_007063191.1	n.550G>A		non_coding_transcript_exon_variant	4/4
SCNN1A	NM_001159576.2	c.1155C>T	p.Asn385=	splice_region_variant, synonymous_variant	4/12		NP_001153048.1
SCNN1A	NM_001159575.2	c.1047C>T	p.Asn349=	splice_region_variant, synonymous_variant	5/13		NP_001153047.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SCNN1A	ENST00000228916.7	c.978C>T	p.Asn326=	splice_region_variant, synonymous_variant	5/13	1	NM_001038.6	ENSP00000228916	A2

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

GnomAD3 exomes AF: 0.00746 AC: 1875 AN: 251496 Hom.: 29 AF XY: 0.00733 AC XY: 996 AN XY: 135922

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 SAS exome AF: 0.0201

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

Gnomad4 AFR exome AF: 0.0466

Gnomad4 AMR exome AF: 0.00286

Gnomad4 ASJ exome AF: 0.0127

Gnomad4 EAS exome AF: 0.00121

Gnomad4 SAS exome AF: 0.0195

Gnomad4 FIN exome AF: 0.00110

Gnomad4 NFE exome AF: 0.00100

Gnomad4 OTH exome AF: 0.00717

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

Gnomad4 AFR AF: 0.0449

Gnomad4 AMR AF: 0.00621

Gnomad4 ASJ AF: 0.0112

Gnomad4 EAS AF: 0.000771

Gnomad4 SAS AF: 0.0201

Gnomad4 FIN AF: 0.00113

Gnomad4 NFE AF: 0.00160

Gnomad4 OTH AF: 0.0142

Alfa AF: 0.00509 Hom.: 17

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

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 23, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 24, 2024	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Bronchiectasis with or without elevated sweat chloride 2 Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 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. -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Nov 26, 2014

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

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.74
CADD	Benign	0.25
DANN	Benign	0.68

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

Publications

LitVar

Other links and lift over

dbSNP: rs61731141; hg19: chr12-6464944;