chr16-23215466-C-G

Variant names:

• chr16-23215466-C-G
• rs5723
• NM_001039.4:c.1947C>G

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001039.4(SCNN1G):​c.1947C>G​(p.Leu649Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.206 in 1,608,242 control chromosomes in the GnomAD database, including 35,956 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.21 (3530 hom., cov: 32)
  • Exomes 𝑓: 0.21 (32426 hom.)
• Consequence: SCNN1G NM_001039.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:13
• Conservation: PhyloP100: 0.124
• Publications: 26 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
• Liddle syndrome 2

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

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

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.78).
• BP6: Variant 16-23215466-C-G is Benign according to our data. Variant chr16-23215466-C-G is described in ClinVar as Benign. ClinVar VariationId is 165177.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.124 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.242 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.1947C>G	p.Leu649Leu	synonymous	Exon 13 of 13	NP_001030.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SCNN1G	ENST00000300061.3	TSL:1 MANE Select	c.1947C>G	p.Leu649Leu	synonymous	Exon 13 of 13	ENSP00000300061.2	P51170
	SCNN1G	ENST00000876142.1		c.1947C>G	p.Leu649Leu	synonymous	Exon 12 of 12	ENSP00000546201.1
	SCNN1G	ENST00000876141.1		c.1923C>G	p.Leu641Leu	synonymous	Exon 13 of 13	ENSP00000546200.1

Frequencies

GnomAD3 genomes AF: 0.212 AC: 32178 AN: 152018 Hom.: 3521 Cov.: 32

Gnomad AFR AF: 0.246

Gnomad AMI AF: 0.197

Gnomad AMR AF: 0.163

Gnomad ASJ AF: 0.227

Gnomad EAS AF: 0.0603

Gnomad SAS AF: 0.0742

Gnomad FIN AF: 0.231

Gnomad MID AF: 0.190

Gnomad NFE AF: 0.220

Gnomad OTH AF: 0.208

GnomAD2 exomes AF: 0.174 AC: 42641 AN: 244838 AF XY: 0.172

Gnomad AFR exome AF: 0.254

Gnomad AMR exome AF: 0.0961

Gnomad ASJ exome AF: 0.233

Gnomad EAS exome AF: 0.0626

Gnomad FIN exome AF: 0.231

Gnomad NFE exome AF: 0.215

Gnomad OTH exome AF: 0.199

GnomAD4 exome AF: 0.205 AC: 298707 AN: 1456106 Hom.: 32426 Cov.: 34 AF XY: 0.202 AC XY: 146193 AN XY: 724636

African (AFR) AF: 0.251 AC: 8418 AN: 33476

American (AMR) AF: 0.105 AC: 4694 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.233 AC: 6096 AN: 26134

East Asian (EAS) AF: 0.0558 AC: 2217 AN: 39698

South Asian (SAS) AF: 0.0845 AC: 7284 AN: 86252

European-Finnish (FIN) AF: 0.223 AC: 10688 AN: 47916

Middle Eastern (MID) AF: 0.185 AC: 1066 AN: 5768

European-Non Finnish (NFE) AF: 0.221 AC: 245790 AN: 1111784

Other (OTH) AF: 0.206 AC: 12454 AN: 60358

GnomAD4 genome AF: 0.212 AC: 32216 AN: 152136 Hom.: 3530 Cov.: 32 AF XY: 0.208 AC XY: 15504 AN XY: 74394

African (AFR) AF: 0.246 AC: 10215 AN: 41506

American (AMR) AF: 0.162 AC: 2484 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.227 AC: 787 AN: 3472

East Asian (EAS) AF: 0.0601 AC: 310 AN: 5162

South Asian (SAS) AF: 0.0742 AC: 358 AN: 4822

European-Finnish (FIN) AF: 0.231 AC: 2450 AN: 10588

Middle Eastern (MID) AF: 0.180 AC: 53 AN: 294

European-Non Finnish (NFE) AF: 0.220 AC: 14926 AN: 67980

Other (OTH) AF: 0.214 AC: 453 AN: 2112

Alfa AF: 0.223 Hom.: 720

Bravo AF: 0.207

Asia WGS AF: 0.110 AC: 382 AN: 3478

EpiCase AF: 0.215

EpiControl AF: 0.209

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	-	4	not specified (4)
-	-	2	Liddle syndrome 2 (2)
-	-	2	Pseudohypoaldosteronism, type IB1, autosomal recessive (2)
-	-	1	Bronchiectasis with or without elevated sweat chloride 3 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.78
CADD	Benign	0.51
DANN	Benign	0.57
PhyloP100		0.12
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: rs5723; hg19: chr16-23226787; COSMIC: COSV55599716; COSMIC: COSV55599716;