NM_001039.4:c.474T>C

Variant names:

• chr16-23189527-T-C
• rs5735
• NM_001039.4:c.474T>C

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.474T>C​(p.Ile158Ile) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.303 in 1,613,964 control chromosomes in the GnomAD database, including 76,419 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.27 (6191 hom., cov: 32)
  • Exomes 𝑓: 0.31 (70228 hom.)
• Consequence: SCNN1G NM_001039.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 0.0660
• Publications: 36 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=-0.76).
• BP6: Variant 16-23189527-T-C is Benign according to our data. Variant chr16-23189527-T-C is described in ClinVar as Benign. ClinVar VariationId is 165173.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.066 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.348 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.474T>C	p.Ile158Ile	synonymous	Exon 3 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.474T>C	p.Ile158Ile	synonymous	Exon 3 of 13	ENSP00000300061.2	P51170
	SCNN1G	ENST00000876142.1		c.474T>C	p.Ile158Ile	synonymous	Exon 2 of 12	ENSP00000546201.1
	SCNN1G	ENST00000876141.1		c.474T>C	p.Ile158Ile	synonymous	Exon 3 of 13	ENSP00000546200.1

Frequencies

GnomAD3 genomes AF: 0.272 AC: 41432 AN: 152052 Hom.: 6168 Cov.: 32

Gnomad AFR AF: 0.157

Gnomad AMI AF: 0.315

Gnomad AMR AF: 0.356

Gnomad ASJ AF: 0.295

Gnomad EAS AF: 0.180

Gnomad SAS AF: 0.266

Gnomad FIN AF: 0.362

Gnomad MID AF: 0.299

Gnomad NFE AF: 0.316

Gnomad OTH AF: 0.276

GnomAD2 exomes AF: 0.309 AC: 77716 AN: 251480 AF XY: 0.305

Gnomad AFR exome AF: 0.157

Gnomad AMR exome AF: 0.436

Gnomad ASJ exome AF: 0.305

Gnomad EAS exome AF: 0.172

Gnomad FIN exome AF: 0.367

Gnomad NFE exome AF: 0.314

Gnomad OTH exome AF: 0.312

GnomAD4 exome AF: 0.306 AC: 447240 AN: 1461796 Hom.: 70228 Cov.: 48 AF XY: 0.305 AC XY: 221951 AN XY: 727206

African (AFR) AF: 0.148 AC: 4949 AN: 33480

American (AMR) AF: 0.431 AC: 19282 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.307 AC: 8016 AN: 26134

East Asian (EAS) AF: 0.162 AC: 6421 AN: 39700

South Asian (SAS) AF: 0.271 AC: 23378 AN: 86258

European-Finnish (FIN) AF: 0.369 AC: 19693 AN: 53414

Middle Eastern (MID) AF: 0.273 AC: 1575 AN: 5768

European-Non Finnish (NFE) AF: 0.311 AC: 345555 AN: 1111924

Other (OTH) AF: 0.304 AC: 18371 AN: 60394

GnomAD4 genome AF: 0.273 AC: 41505 AN: 152168 Hom.: 6191 Cov.: 32 AF XY: 0.275 AC XY: 20417 AN XY: 74374

African (AFR) AF: 0.158 AC: 6559 AN: 41536

American (AMR) AF: 0.356 AC: 5444 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.295 AC: 1025 AN: 3470

East Asian (EAS) AF: 0.180 AC: 931 AN: 5176

South Asian (SAS) AF: 0.268 AC: 1289 AN: 4812

European-Finnish (FIN) AF: 0.362 AC: 3832 AN: 10584

Middle Eastern (MID) AF: 0.301 AC: 88 AN: 292

European-Non Finnish (NFE) AF: 0.316 AC: 21469 AN: 67984

Other (OTH) AF: 0.275 AC: 581 AN: 2116

Alfa AF: 0.301 Hom.: 11276

Bravo AF: 0.269

Asia WGS AF: 0.274 AC: 950 AN: 3478

EpiCase AF: 0.306

EpiControl AF: 0.307

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	-	2	not specified (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	-0.76
CADD	Benign	5.1
DANN	Benign	0.59
PhyloP100		0.066
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: rs5735; hg19: chr16-23200848; COSMIC: COSV55597765;