12-6349108-G-C

Variant names:

• chr12-6349108-G-C
• rs3764874
• NM_001038.6:c.1497+56C>G

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.1497+56C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.222 in 1,602,410 control chromosomes in the GnomAD database, including 40,417 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.20 (3113 hom., cov: 31)
  • Exomes 𝑓: 0.22 (37304 hom.)
• Consequence: SCNN1A NM_001038.6 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.342
• Publications: 16 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

LOC107984500 (HGNC:):

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP6: Variant 12-6349108-G-C is Benign according to our data. Variant chr12-6349108-G-C is described in ClinVar as Benign. ClinVar VariationId is 1271585.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.272 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SCNN1A	NM_001038.6	MANE Select	c.1497+56C>G		intron	N/A	NP_001029.1
	SCNN1A	NM_001159576.2		c.1674+56C>G		intron	N/A	NP_001153048.1
	SCNN1A	NM_001159575.2		c.1566+56C>G		intron	N/A	NP_001153047.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SCNN1A	ENST00000228916.7	TSL:1 MANE Select	c.1497+56C>G		intron	N/A	ENSP00000228916.2
	SCNN1A	ENST00000360168.7	TSL:1	c.1674+56C>G		intron	N/A	ENSP00000353292.3
	SCNN1A	ENST00000540037.5	TSL:1	c.597+56C>G		intron	N/A	ENSP00000440876.1

Frequencies

GnomAD3 genomes AF: 0.199 AC: 30179 AN: 151914 Hom.: 3109 Cov.: 31

Gnomad AFR AF: 0.151

Gnomad AMI AF: 0.377

Gnomad AMR AF: 0.158

Gnomad ASJ AF: 0.193

Gnomad EAS AF: 0.129

Gnomad SAS AF: 0.285

Gnomad FIN AF: 0.227

Gnomad MID AF: 0.174

Gnomad NFE AF: 0.230

Gnomad OTH AF: 0.186

GnomAD4 exome AF: 0.224 AC: 324898 AN: 1450378 Hom.: 37304 Cov.: 29 AF XY: 0.226 AC XY: 163077 AN XY: 722360

African (AFR) AF: 0.145 AC: 4816 AN: 33262

American (AMR) AF: 0.169 AC: 7548 AN: 44710

Ashkenazi Jewish (ASJ) AF: 0.188 AC: 4889 AN: 26062

East Asian (EAS) AF: 0.150 AC: 5932 AN: 39630

South Asian (SAS) AF: 0.284 AC: 24403 AN: 86006

European-Finnish (FIN) AF: 0.227 AC: 12098 AN: 53400

Middle Eastern (MID) AF: 0.198 AC: 1077 AN: 5448

European-Non Finnish (NFE) AF: 0.228 AC: 251098 AN: 1101878

Other (OTH) AF: 0.217 AC: 13037 AN: 59982

GnomAD4 genome AF: 0.199 AC: 30193 AN: 152032 Hom.: 3113 Cov.: 31 AF XY: 0.201 AC XY: 14904 AN XY: 74322

African (AFR) AF: 0.151 AC: 6263 AN: 41478

American (AMR) AF: 0.158 AC: 2413 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.193 AC: 670 AN: 3472

East Asian (EAS) AF: 0.129 AC: 667 AN: 5180

South Asian (SAS) AF: 0.285 AC: 1373 AN: 4820

European-Finnish (FIN) AF: 0.227 AC: 2403 AN: 10566

Middle Eastern (MID) AF: 0.177 AC: 52 AN: 294

European-Non Finnish (NFE) AF: 0.230 AC: 15617 AN: 67918

Other (OTH) AF: 0.185 AC: 392 AN: 2116

Alfa AF: 0.128 Hom.: 264

Bravo AF: 0.187

Asia WGS AF: 0.217 AC: 755 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Sep 06, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	0.49
DANN	Benign	0.55
PhyloP100		-0.34
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: rs3764874; hg19: chr12-6458274;