rs5742912

Variant names:

• chr12-6349184-A-G
• rs5742912
• NM_001038.6:c.1477T>C

Your query was ambiguous. Multiple possible variants found:

• chr12-6349184-A-G
• chr12-6349184-A-T

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 1P and 20B. PP3 BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001038.6(SCNN1A):​c.1477T>C​(p.Trp493Arg) variant causes a missense change. The variant allele was found at a frequency of 0.0206 in 1,614,044 control chromosomes in the GnomAD database, including 433 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. W493G) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.017 (47 hom., cov: 31)
  • Exomes 𝑓: 0.021 (386 hom.)
• Consequence: SCNN1A NM_001038.6 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts P:1 B:11
• Conservation: PhyloP100: 5.64
• Publications: 42 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 -19 ACMG points.

• PP3: Multiple lines of computational evidence support a deleterious effect 6: AlphaMissense, BayesDel_noAF, Cadd, Eigen, MutationAssessor, PROVEAN [when max_spliceai, FATHMM_MKL, MetaRNN, MutationTaster was below the threshold]
• BP4: Computational evidence support a benign effect (MetaRNN=0.015588254).
• BP6: Variant 12-6349184-A-G is Benign according to our data. Variant chr12-6349184-A-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 9269.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.0167 (2542/152256) while in subpopulation AMR AF = 0.0255 (390/15294). AF 95% confidence interval is 0.0234. There are 47 homozygotes in GnomAd4. There are 1201 alleles in the male GnomAd4 subpopulation. Median coverage is 31. 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.1477T>C	p.Trp493Arg	missense	Exon 10 of 13	NP_001029.1	P37088-1
	SCNN1A	NM_001159576.2		c.1654T>C	p.Trp552Arg	missense	Exon 9 of 12	NP_001153048.1	P37088-2
	SCNN1A	NM_001159575.2		c.1546T>C	p.Trp516Arg	missense	Exon 10 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.1477T>C	p.Trp493Arg	missense	Exon 10 of 13	ENSP00000228916.2	P37088-1
	SCNN1A	ENST00000360168.7	TSL:1	c.1654T>C	p.Trp552Arg	missense	Exon 9 of 12	ENSP00000353292.3	P37088-2
	SCNN1A	ENST00000540037.5	TSL:1	c.577T>C	p.Trp193Arg	missense	Exon 8 of 11	ENSP00000440876.1	F5GXE6

Frequencies

GnomAD3 genomes AF: 0.0167 AC: 2545 AN: 152138 Hom.: 47 Cov.: 31

Gnomad AFR AF: 0.00403

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0256

Gnomad ASJ AF: 0.0185

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.0191

Gnomad FIN AF: 0.0128

Gnomad MID AF: 0.0222

Gnomad NFE AF: 0.0241

Gnomad OTH AF: 0.0244

GnomAD2 exomes AF: 0.0192 AC: 4833 AN: 251454 AF XY: 0.0203

Gnomad AFR exome AF: 0.00394

Gnomad AMR exome AF: 0.0228

Gnomad ASJ exome AF: 0.0146

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0134

Gnomad NFE exome AF: 0.0229

Gnomad OTH exome AF: 0.0238

GnomAD4 exome AF: 0.0210 AC: 30761 AN: 1461788 Hom.: 386 Cov.: 33 AF XY: 0.0217 AC XY: 15790 AN XY: 727202

African (AFR) AF: 0.00364 AC: 122 AN: 33480

American (AMR) AF: 0.0223 AC: 999 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0160 AC: 418 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.0247 AC: 2129 AN: 86252

European-Finnish (FIN) AF: 0.0127 AC: 677 AN: 53416

Middle Eastern (MID) AF: 0.0235 AC: 135 AN: 5738

European-Non Finnish (NFE) AF: 0.0226 AC: 25122 AN: 1111954

Other (OTH) AF: 0.0192 AC: 1159 AN: 60388

GnomAD4 genome AF: 0.0167 AC: 2542 AN: 152256 Hom.: 47 Cov.: 31 AF XY: 0.0161 AC XY: 1201 AN XY: 74454

African (AFR) AF: 0.00399 AC: 166 AN: 41570

American (AMR) AF: 0.0255 AC: 390 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.0185 AC: 64 AN: 3468

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5188

South Asian (SAS) AF: 0.0191 AC: 92 AN: 4820

European-Finnish (FIN) AF: 0.0128 AC: 136 AN: 10598

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

European-Non Finnish (NFE) AF: 0.0241 AC: 1636 AN: 68002

Other (OTH) AF: 0.0242 AC: 51 AN: 2110

Alfa AF: 0.0210 Hom.: 137

Bravo AF: 0.0169

TwinsUK AF: 0.0159 AC: 59

ALSPAC AF: 0.0244 AC: 94

ESP6500AA AF: 0.00522 AC: 23

ESP6500EA AF: 0.0237 AC: 204

ExAC AF: 0.0182 AC: 2214

Asia WGS AF: 0.0110 AC: 40 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not specified (5)
-	-	4	not provided (4)
1	-	1	Bronchiectasis with or without elevated sweat chloride 2 (2)
-	-	1	Pseudohypoaldosteronism, type IB1, autosomal recessive (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Uncertain	0.024	T
BayesDel_noAF	Pathogenic	0.28
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.68	D
Eigen	Pathogenic	0.81
Eigen_PC	Pathogenic	0.73
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Benign	0.82	T
MetaRNN	Benign	0.016	T
MetaSVM	Uncertain	0.047	D
MutationAssessor	Pathogenic	3.2	M
PhyloP100		5.6
PrimateAI	Uncertain	0.65	T
PROVEAN	Pathogenic	-13	D
REVEL	Uncertain	0.50
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.42
MutPred		0.32		Gain of disorder (P = 0.0045)
MPC		0.75
ClinPred		0.093	T
GERP RS		5.2
Varity_R		0.93
gMVP		0.88
Mutation Taster		=82/18	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
Splicevardb		2.0
SpliceAI score (max)		0.010		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: rs5742912; hg19: chr12-6458350; COSMIC: COSV107211286; COSMIC: COSV107211286;