rs3741913

Variant names:

• chr12-6348030-C-A
• rs3741913
• NM_001038.6:c.1853G>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001038.6(SCNN1A):​c.1853G>T​(p.Cys618Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0059 in 1,603,002 control chromosomes in the GnomAD database, including 385 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.028 (186 hom., cov: 29)
  • Exomes 𝑓: 0.0036 (199 hom.)
• Consequence: SCNN1A NM_001038.6 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 0.583
• Publications: 15 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, 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

LOC107984500 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0019331872).
• BP6: Variant 12-6348030-C-A is Benign according to our data. Variant chr12-6348030-C-A is described in ClinVar as Benign. ClinVar VariationId is 194190.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0907 is higher than 0.05.

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.1853G>T	p.Cys618Phe	missense	Exon 13 of 13	NP_001029.1
	SCNN1A	NM_001159576.2		c.2030G>T	p.Cys677Phe	missense	Exon 12 of 12	NP_001153048.1
	SCNN1A	NM_001159575.2		c.1922G>T	p.Cys641Phe	missense	Exon 13 of 13	NP_001153047.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SCNN1A	ENST00000228916.7	TSL:1 MANE Select	c.1853G>T	p.Cys618Phe	missense	Exon 13 of 13	ENSP00000228916.2
	SCNN1A	ENST00000360168.7	TSL:1	c.2030G>T	p.Cys677Phe	missense	Exon 12 of 12	ENSP00000353292.3
	SCNN1A	ENST00000540037.5	TSL:1	c.953G>T	p.Cys318Phe	missense	Exon 11 of 11	ENSP00000440876.1

Frequencies

GnomAD3 genomes AF: 0.0276 AC: 4196 AN: 152102 Hom.: 185 Cov.: 29

Gnomad AFR AF: 0.0930

Gnomad AMI AF: 0.0154

Gnomad AMR AF: 0.0119

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0119

Gnomad SAS AF: 0.00186

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0190

Gnomad NFE AF: 0.000441

Gnomad OTH AF: 0.0202

GnomAD2 exomes AF: 0.00706 AC: 1614 AN: 228504 AF XY: 0.00525

Gnomad AFR exome AF: 0.0890

Gnomad AMR exome AF: 0.00449

Gnomad ASJ exome AF: 0.000105

Gnomad EAS exome AF: 0.00366

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000337

Gnomad OTH exome AF: 0.00492

GnomAD4 exome AF: 0.00361 AC: 5239 AN: 1450782 Hom.: 199 Cov.: 34 AF XY: 0.00318 AC XY: 2292 AN XY: 720968

African (AFR) AF: 0.0955 AC: 3162 AN: 33110

American (AMR) AF: 0.00524 AC: 224 AN: 42742

Ashkenazi Jewish (ASJ) AF: 0.0000387 AC: 1 AN: 25810

East Asian (EAS) AF: 0.0242 AC: 946 AN: 39074

South Asian (SAS) AF: 0.00193 AC: 164 AN: 85024

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52584

Middle Eastern (MID) AF: 0.00626 AC: 36 AN: 5752

European-Non Finnish (NFE) AF: 0.000257 AC: 284 AN: 1106718

Other (OTH) AF: 0.00704 AC: 422 AN: 59968

GnomAD4 genome AF: 0.0277 AC: 4211 AN: 152220 Hom.: 186 Cov.: 29 AF XY: 0.0266 AC XY: 1977 AN XY: 74422

African (AFR) AF: 0.0931 AC: 3867 AN: 41524

American (AMR) AF: 0.0119 AC: 182 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.0120 AC: 62 AN: 5180

South Asian (SAS) AF: 0.00166 AC: 8 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10602

Middle Eastern (MID) AF: 0.0204 AC: 6 AN: 294

European-Non Finnish (NFE) AF: 0.000441 AC: 30 AN: 67998

Other (OTH) AF: 0.0200 AC: 42 AN: 2104

Alfa AF: 0.00533 Hom.: 44

Bravo AF: 0.0315

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.0895 AC: 394

ESP6500EA AF: 0.000582 AC: 5

ExAC AF: 0.00836 AC: 1014

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.075
BayesDel_addAF	Benign	-0.43	T
BayesDel_noAF	Benign	-0.33
CADD	Benign	20
DANN	Uncertain	0.98
DEOGEN2	Benign	0.27	T
Eigen	Uncertain	0.30
Eigen_PC	Uncertain	0.24
FATHMM_MKL	Uncertain	0.82	D
LIST_S2	Benign	0.70	T
MetaRNN	Benign	0.0019	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.5	M
PhyloP100		0.58
PrimateAI	Benign	0.43	T
PROVEAN	Benign	-2.0	N
REVEL	Benign	0.24
Sift	Benign	0.48	T
Sift4G	Uncertain	0.037	D
Polyphen		1.0	D
Vest4		0.18
MVP		0.84
MPC		0.34
ClinPred		0.022	T
GERP RS		2.8
Varity_R		0.17
gMVP		0.43
Mutation Taster		=96/4	polymorphism (auto)

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

Other links and lift over

dbSNP: rs3741913; hg19: chr12-6457196; COSMIC: COSV57436610; COSMIC: COSV57436610;