12-6354776-G-T

Variant names:

• chr12-6354776-G-T
• rs149484264
• NM_001038.6:c.1216C>A

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4_Strong BP6

The NM_001038.6(SCNN1A):​c.1216C>A​(p.Leu406Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000286 in 1,613,932 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00029 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00029 (0 hom.)
• Consequence: SCNN1A NM_001038.6 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5 B:2
• Conservation: PhyloP100: 1.35
• 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: Likely_benign. The variant received -5 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.019364148).
• BP6: Variant 12-6354776-G-T is Benign according to our data. Variant chr12-6354776-G-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 229238.

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.1216C>A	p.Leu406Ile	missense	Exon 7 of 13	NP_001029.1	P37088-1
	SCNN1A	NM_001159576.2		c.1393C>A	p.Leu465Ile	missense	Exon 6 of 12	NP_001153048.1	P37088-2
	SCNN1A	NM_001159575.2		c.1285C>A	p.Leu429Ile	missense	Exon 7 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.1216C>A	p.Leu406Ile	missense	Exon 7 of 13	ENSP00000228916.2	P37088-1
	SCNN1A	ENST00000360168.7	TSL:1	c.1393C>A	p.Leu465Ile	missense	Exon 6 of 12	ENSP00000353292.3	P37088-2
	SCNN1A	ENST00000540037.5	TSL:1	c.316C>A	p.Leu106Ile	missense	Exon 5 of 11	ENSP00000440876.1	F5GXE6

Frequencies

GnomAD3 genomes AF: 0.000290 AC: 44 AN: 151984 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000242

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00722

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000250

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.000354 AC: 89 AN: 251486 AF XY: 0.000258

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000578

Gnomad ASJ exome AF: 0.00655

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000158

Gnomad OTH exome AF: 0.000489

GnomAD4 exome AF: 0.000286 AC: 418 AN: 1461830 Hom.: 0 Cov.: 32 AF XY: 0.000274 AC XY: 199 AN XY: 727220

African (AFR) AF: 0.0000597 AC: 2 AN: 33480

American (AMR) AF: 0.0000447 AC: 2 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00892 AC: 233 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39694

South Asian (SAS) AF: 0.00 AC: 0 AN: 86254

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53416

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.000135 AC: 150 AN: 1111968

Other (OTH) AF: 0.000513 AC: 31 AN: 60394

GnomAD4 genome AF: 0.000289 AC: 44 AN: 152102 Hom.: 0 Cov.: 32 AF XY: 0.000269 AC XY: 20 AN XY: 74346

African (AFR) AF: 0.0000241 AC: 1 AN: 41474

American (AMR) AF: 0.00 AC: 0 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.00722 AC: 25 AN: 3462

East Asian (EAS) AF: 0.00 AC: 0 AN: 5168

South Asian (SAS) AF: 0.00 AC: 0 AN: 4802

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10612

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000250 AC: 17 AN: 67986

Other (OTH) AF: 0.000473 AC: 1 AN: 2112

Alfa AF: 0.000515 Hom.: 2

Bravo AF: 0.000393

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000698 AC: 6

ExAC AF: 0.000280 AC: 34

EpiCase AF: 0.000382

EpiControl AF: 0.000237

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	2	-	Bronchiectasis with or without elevated sweat chloride 2;C4748292:Liddle syndrome 3;C5774176:Pseudohypoaldosteronism, type IB1, autosomal recessive (2)
-	-	1	Bronchiectasis with or without elevated sweat chloride 2 (1)
-	1	-	Inborn genetic diseases (1)
-	-	1	not provided (1)
-	1	-	not specified (1)
-	1	-	Pseudohypoaldosteronism, type IB1, autosomal recessive (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.085
BayesDel_addAF	Benign	-0.30	T
BayesDel_noAF	Benign	-0.41
CADD	Benign	18
DANN	Uncertain	0.99
DEOGEN2	Benign	0.21	T
Eigen	Benign	0.14
Eigen_PC	Benign	0.15
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Benign	0.72	T
M_CAP	Benign	0.026	D
MetaRNN	Benign	0.019	T
MetaSVM	Benign	-0.72	T
MutationAssessor	Benign	1.4	L
PhyloP100		1.3
PrimateAI	Benign	0.47	T
PROVEAN	Benign	-1.4	N
REVEL	Benign	0.23
Sift	Benign	0.23	T
Sift4G	Benign	0.15	T
Polyphen		0.83	P
Vest4		0.22
MVP		0.78
MPC		0.33
ClinPred		0.073	T
GERP RS		2.1
Varity_R		0.18
gMVP		0.52
Mutation Taster		=83/17	polymorphism

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: rs149484264; hg19: chr12-6463942;