rs11542844

Variant names:

• chr12-6355415-C-T
• rs11542844
• NM_001038.6:c.1000G>A

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.1000G>A​(p.Ala334Thr) variant causes a missense change. The variant allele was found at a frequency of 0.0643 in 1,613,752 control chromosomes in the GnomAD database, including 10,382 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar.

• Frequency:
  • Genomes: 𝑓 0.16 (4579 hom., cov: 32)
  • Exomes 𝑓: 0.054 (5803 hom.)
• Consequence: SCNN1A NM_001038.6 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 4.32
• Publications: 33 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0010077357).
• BP6: Variant 12-6355415-C-T is Benign according to our data. Variant chr12-6355415-C-T is described in ClinVar as Benign. ClinVar VariationId is 165165.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.45 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.1000G>A	p.Ala334Thr	missense	Exon 6 of 13	NP_001029.1	P37088-1
	SCNN1A	NM_001159576.2		c.1177G>A	p.Ala393Thr	missense	Exon 5 of 12	NP_001153048.1	P37088-2
	SCNN1A	NM_001159575.2		c.1069G>A	p.Ala357Thr	missense	Exon 6 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.1000G>A	p.Ala334Thr	missense	Exon 6 of 13	ENSP00000228916.2	P37088-1
	SCNN1A	ENST00000360168.7	TSL:1	c.1177G>A	p.Ala393Thr	missense	Exon 5 of 12	ENSP00000353292.3	P37088-2
	SCNN1A	ENST00000540037.5	TSL:1	c.100G>A	p.Ala34Thr	missense	Exon 4 of 11	ENSP00000440876.1	F5GXE6

Frequencies

GnomAD3 genomes AF: 0.164 AC: 24999 AN: 152128 Hom.: 4555 Cov.: 32

Gnomad AFR AF: 0.455

Gnomad AMI AF: 0.00219

Gnomad AMR AF: 0.0726

Gnomad ASJ AF: 0.0354

Gnomad EAS AF: 0.148

Gnomad SAS AF: 0.0585

Gnomad FIN AF: 0.105

Gnomad MID AF: 0.0759

Gnomad NFE AF: 0.0367

Gnomad OTH AF: 0.117

GnomAD2 exomes AF: 0.0794 AC: 19801 AN: 249434 AF XY: 0.0714

Gnomad AFR exome AF: 0.458

Gnomad AMR exome AF: 0.0307

Gnomad ASJ exome AF: 0.0459

Gnomad EAS exome AF: 0.140

Gnomad FIN exome AF: 0.0999

Gnomad NFE exome AF: 0.0388

Gnomad OTH exome AF: 0.0554

GnomAD4 exome AF: 0.0539 AC: 78762 AN: 1461506 Hom.: 5803 Cov.: 33 AF XY: 0.0525 AC XY: 38171 AN XY: 727010

African (AFR) AF: 0.482 AC: 16134 AN: 33464

American (AMR) AF: 0.0357 AC: 1594 AN: 44690

Ashkenazi Jewish (ASJ) AF: 0.0437 AC: 1141 AN: 26128

East Asian (EAS) AF: 0.146 AC: 5806 AN: 39690

South Asian (SAS) AF: 0.0485 AC: 4185 AN: 86200

European-Finnish (FIN) AF: 0.0974 AC: 5191 AN: 53300

Middle Eastern (MID) AF: 0.0685 AC: 395 AN: 5768

European-Non Finnish (NFE) AF: 0.0362 AC: 40226 AN: 1111886

Other (OTH) AF: 0.0677 AC: 4090 AN: 60380

GnomAD4 genome AF: 0.165 AC: 25079 AN: 152246 Hom.: 4579 Cov.: 32 AF XY: 0.164 AC XY: 12214 AN XY: 74450

African (AFR) AF: 0.456 AC: 18918 AN: 41500

American (AMR) AF: 0.0724 AC: 1108 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.0354 AC: 123 AN: 3472

East Asian (EAS) AF: 0.149 AC: 769 AN: 5176

South Asian (SAS) AF: 0.0581 AC: 281 AN: 4834

European-Finnish (FIN) AF: 0.105 AC: 1114 AN: 10606

Middle Eastern (MID) AF: 0.0782 AC: 23 AN: 294

European-Non Finnish (NFE) AF: 0.0366 AC: 2492 AN: 68034

Other (OTH) AF: 0.118 AC: 249 AN: 2112

Alfa AF: 0.0733 Hom.: 5009

Bravo AF: 0.177

TwinsUK AF: 0.0380 AC: 141

ALSPAC AF: 0.0376 AC: 145

ESP6500AA AF: 0.448 AC: 1975

ESP6500EA AF: 0.0370 AC: 318

ExAC AF: 0.0864 AC: 10495

Asia WGS AF: 0.125 AC: 438 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	2	not specified (2)
-	-	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	0.048
BayesDel_addAF	Benign	-0.62	T
BayesDel_noAF	Benign	-0.51
CADD	Benign	18
DANN	Benign	0.92
DEOGEN2	Benign	0.091	T
Eigen	Benign	-0.86
Eigen_PC	Benign	-0.57
FATHMM_MKL	Benign	0.15	N
LIST_S2	Benign	0.46	T
MetaRNN	Benign	0.0010	T
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	-1.5	N
PhyloP100		4.3
PrimateAI	Uncertain	0.49	T
PROVEAN	Benign	1.6	N
REVEL	Benign	0.076
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.0020	B
Vest4		0.19
MPC		0.11
ClinPred		0.0044	T
GERP RS		3.7
Varity_R		0.11
gMVP		0.50
Mutation Taster		=98/2	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs11542844; hg19: chr12-6464581; COSMIC: COSV99057035; COSMIC: COSV99057035;