16-23186224-C-G

Variant names:

• chr16-23186224-C-G
• rs5731
• NM_001039.4:c.-44-4C>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001039.4(SCNN1G):​c.-44-4C>G variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.23 in 1,593,792 control chromosomes in the GnomAD database, including 44,130 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.21 (3597 hom., cov: 32)
  • Exomes 𝑓: 0.23 (40533 hom.)
• Consequence: SCNN1G NM_001039.4 splice_region, intron
• Scores: Splicing: ADA: 0.0004556
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.440
• Publications: 8 publications found

Genes affected

SCNN1G (HGNC:10602): (sodium channel epithelial 1 subunit gamma) 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 gamma subunit, and mutations in this gene have been associated with Liddle syndrome. [provided by RefSeq, Apr 2009]

SCNN1G Gene-Disease associations (from GenCC):

• Liddle syndrome

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
• bronchiectasis with or without elevated sweat chloride 3

  Inheritance: AD Classification: STRONG Submitted by: PanelApp Australia
• Liddle syndrome 2

  Inheritance: AD Classification: STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, Laboratory for Molecular Medicine
• pseudohypoaldosteronism, type IB1, autosomal recessive

  Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet

ENSG00000285613 (HGNC:):

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.78).
• BP6: Variant 16-23186224-C-G is Benign according to our data. Variant chr16-23186224-C-G is described in ClinVar as Benign. ClinVar VariationId is 318343.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.299 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001039.4. 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
	SCNN1G	NM_001039.4	MANE Select	c.-44-4C>G		splice_region intron	N/A	NP_001030.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SCNN1G	ENST00000300061.3	TSL:1 MANE Select	c.-44-4C>G		splice_region intron	N/A	ENSP00000300061.2	P51170
	SCNN1G	ENST00000876142.1		c.-48C>G		5_prime_UTR_premature_start_codon_gain	Exon 1 of 12	ENSP00000546201.1
	SCNN1G	ENST00000876142.1		c.-48C>G		5_prime_UTR	Exon 1 of 12	ENSP00000546201.1

Frequencies

GnomAD3 genomes AF: 0.207 AC: 31452 AN: 152050 Hom.: 3579 Cov.: 32

Gnomad AFR AF: 0.117

Gnomad AMI AF: 0.289

Gnomad AMR AF: 0.306

Gnomad ASJ AF: 0.246

Gnomad EAS AF: 0.159

Gnomad SAS AF: 0.220

Gnomad FIN AF: 0.239

Gnomad MID AF: 0.244

Gnomad NFE AF: 0.234

Gnomad OTH AF: 0.210

GnomAD2 exomes AF: 0.242 AC: 59816 AN: 247326 AF XY: 0.237

Gnomad AFR exome AF: 0.117

Gnomad AMR exome AF: 0.393

Gnomad ASJ exome AF: 0.245

Gnomad EAS exome AF: 0.151

Gnomad FIN exome AF: 0.245

Gnomad NFE exome AF: 0.231

Gnomad OTH exome AF: 0.237

GnomAD4 exome AF: 0.233 AC: 335672 AN: 1441624 Hom.: 40533 Cov.: 28 AF XY: 0.233 AC XY: 167283 AN XY: 718428

African (AFR) AF: 0.114 AC: 3752 AN: 33034

American (AMR) AF: 0.389 AC: 17267 AN: 44386

Ashkenazi Jewish (ASJ) AF: 0.249 AC: 6486 AN: 26012

East Asian (EAS) AF: 0.145 AC: 5753 AN: 39606

South Asian (SAS) AF: 0.231 AC: 19739 AN: 85474

European-Finnish (FIN) AF: 0.243 AC: 12972 AN: 53300

Middle Eastern (MID) AF: 0.198 AC: 1131 AN: 5724

European-Non Finnish (NFE) AF: 0.233 AC: 254774 AN: 1094406

Other (OTH) AF: 0.231 AC: 13798 AN: 59682

GnomAD4 genome AF: 0.207 AC: 31500 AN: 152168 Hom.: 3597 Cov.: 32 AF XY: 0.208 AC XY: 15466 AN XY: 74410

African (AFR) AF: 0.117 AC: 4879 AN: 41552

American (AMR) AF: 0.307 AC: 4691 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.246 AC: 854 AN: 3470

East Asian (EAS) AF: 0.159 AC: 823 AN: 5188

South Asian (SAS) AF: 0.222 AC: 1073 AN: 4826

European-Finnish (FIN) AF: 0.239 AC: 2528 AN: 10588

Middle Eastern (MID) AF: 0.245 AC: 72 AN: 294

European-Non Finnish (NFE) AF: 0.234 AC: 15876 AN: 67936

Other (OTH) AF: 0.209 AC: 441 AN: 2110

Alfa AF: 0.166 Hom.: 489

Bravo AF: 0.211

Asia WGS AF: 0.193 AC: 668 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Liddle syndrome 2 (1)
-	-	1	Pseudohypoaldosteronism, type IB1, autosomal recessive (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.78
CADD	Benign	12
DANN	Benign	0.41
PhyloP100		-0.44
Mutation Taster		=93/7	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00046
dbscSNV1_RF	Benign	0.0040
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: rs5731; hg19: chr16-23197545; COSMIC: COSV55597782;