NM_001038.6:c.416+4242T>G

Variant names:

• chr12-6370126-A-C
• rs10849446
• NM_001038.6:c.416+4242T>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001038.6(SCNN1A):​c.416+4242T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.417 in 152,028 control chromosomes in the GnomAD database, including 16,306 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.42 (16306 hom., cov: 32)
• Consequence: SCNN1A NM_001038.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.926
• Publications: 11 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, Laboratory for Molecular Medicine, Orphanet, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• bronchiectasis with or without elevated sweat chloride 2

  Inheritance: Unknown, AD Classification: STRONG, 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

LOC105369626 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.576 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SCNN1A	NM_001038.6	c.416+4242T>G		intron_variant	Intron 2 of 12	ENST00000228916.7	NP_001029.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SCNN1A	ENST00000228916.7	c.416+4242T>G		intron_variant	Intron 2 of 12	1	NM_001038.6	ENSP00000228916.2

Frequencies

GnomAD3 genomes AF: 0.418 AC: 63427 AN: 151910 Hom.: 16317 Cov.: 32

Gnomad AFR AF: 0.145

Gnomad AMI AF: 0.652

Gnomad AMR AF: 0.388

Gnomad ASJ AF: 0.779

Gnomad EAS AF: 0.112

Gnomad SAS AF: 0.358

Gnomad FIN AF: 0.493

Gnomad MID AF: 0.668

Gnomad NFE AF: 0.581

Gnomad OTH AF: 0.491

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.417 AC: 63414 AN: 152028 Hom.: 16306 Cov.: 32 AF XY: 0.410 AC XY: 30484 AN XY: 74296

African (AFR) AF: 0.144 AC: 5989 AN: 41462

American (AMR) AF: 0.387 AC: 5902 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.779 AC: 2704 AN: 3470

East Asian (EAS) AF: 0.111 AC: 573 AN: 5164

South Asian (SAS) AF: 0.359 AC: 1727 AN: 4812

European-Finnish (FIN) AF: 0.493 AC: 5207 AN: 10560

Middle Eastern (MID) AF: 0.663 AC: 195 AN: 294

European-Non Finnish (NFE) AF: 0.581 AC: 39489 AN: 67970

Other (OTH) AF: 0.488 AC: 1033 AN: 2116

Alfa AF: 0.518 Hom.: 52671

Bravo AF: 0.399

Asia WGS AF: 0.231 AC: 809 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	0.41
DANN	Benign	0.78
PhyloP100		-0.93
Mutation Taster		=100/0	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: rs10849446; hg19: chr12-6479292;