rs61731141

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: 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

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

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SCNN1A	NM_001038.6	MANE Select	c.978C>T	p.Asn326Asn	splice_region synonymous	Exon 5 of 13	NP_001029.1	P37088-1
	SCNN1A	NM_001159576.2		c.1155C>T	p.Asn385Asn	splice_region synonymous	Exon 4 of 12	NP_001153048.1	P37088-2
	SCNN1A	NM_001159575.2		c.1047C>T	p.Asn349Asn	splice_region synonymous	Exon 5 of 13	NP_001153047.1	P37088-6

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SCNN1A	ENST00000228916.7	TSL:1 MANE Select	c.978C>T	p.Asn326Asn	splice_region synonymous	Exon 5 of 13	ENSP00000228916.2	P37088-1
	SCNN1A	ENST00000360168.7	TSL:1	c.1155C>T	p.Asn385Asn	splice_region synonymous	Exon 4 of 12	ENSP00000353292.3	P37088-2
	SCNN1A	ENST00000540037.5	TSL:1	c.78C>T	p.Asn26Asn	splice_region synonymous	Exon 3 of 11	ENSP00000440876.1	F5GXE6

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

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	1	Bronchiectasis with or without elevated sweat chloride 2 (1)
-	-	1	not specified (1)
-	-	1	Pseudohypoaldosteronism, type IB1, autosomal recessive (1)

Computational scores

Source: dbNSFP v4.9

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;