rs5739

Variant names:

• chr16-23192369-C-T
• rs5739
• NM_001039.4:c.636C>T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_001039.4(SCNN1G):​c.636C>T​(p.Ser212Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0212 in 1,613,838 control chromosomes in the GnomAD database, including 487 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.018 (52 hom., cov: 31)
  • Exomes 𝑓: 0.022 (435 hom.)
• Consequence: SCNN1G NM_001039.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: -3.12
• Publications: 13 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=-0.81).
• BP6: Variant 16-23192369-C-T is Benign according to our data. Variant chr16-23192369-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 178805.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-3.12 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0176 (2673/152272) while in subpopulation NFE AF = 0.0264 (1798/68022). AF 95% confidence interval is 0.0254. There are 52 homozygotes in GnomAd4. There are 1305 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 52 AD,AR gene

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.636C>T	p.Ser212Ser	synonymous	Exon 4 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.636C>T	p.Ser212Ser	synonymous	Exon 4 of 13	ENSP00000300061.2	P51170
	SCNN1G	ENST00000876142.1		c.636C>T	p.Ser212Ser	synonymous	Exon 3 of 12	ENSP00000546201.1
	SCNN1G	ENST00000876141.1		c.636C>T	p.Ser212Ser	synonymous	Exon 4 of 13	ENSP00000546200.1

Frequencies

GnomAD3 genomes AF: 0.0176 AC: 2676 AN: 152154 Hom.: 52 Cov.: 31

Gnomad AFR AF: 0.00403

Gnomad AMI AF: 0.00768

Gnomad AMR AF: 0.0142

Gnomad ASJ AF: 0.0233

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00705

Gnomad FIN AF: 0.0290

Gnomad MID AF: 0.0316

Gnomad NFE AF: 0.0264

Gnomad OTH AF: 0.0254

GnomAD2 exomes AF: 0.0192 AC: 4835 AN: 251460 AF XY: 0.0196

Gnomad AFR exome AF: 0.00332

Gnomad AMR exome AF: 0.0123

Gnomad ASJ exome AF: 0.0275

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.0316

Gnomad NFE exome AF: 0.0268

Gnomad OTH exome AF: 0.0221

GnomAD4 exome AF: 0.0216 AC: 31615 AN: 1461566 Hom.: 435 Cov.: 32 AF XY: 0.0214 AC XY: 15542 AN XY: 727092

African (AFR) AF: 0.00350 AC: 117 AN: 33472

American (AMR) AF: 0.0126 AC: 562 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0250 AC: 652 AN: 26128

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39698

South Asian (SAS) AF: 0.00701 AC: 605 AN: 86252

European-Finnish (FIN) AF: 0.0352 AC: 1881 AN: 53420

Middle Eastern (MID) AF: 0.0405 AC: 233 AN: 5750

European-Non Finnish (NFE) AF: 0.0237 AC: 26339 AN: 1111742

Other (OTH) AF: 0.0203 AC: 1225 AN: 60380

GnomAD4 genome AF: 0.0176 AC: 2673 AN: 152272 Hom.: 52 Cov.: 31 AF XY: 0.0175 AC XY: 1305 AN XY: 74452

African (AFR) AF: 0.00402 AC: 167 AN: 41558

American (AMR) AF: 0.0142 AC: 217 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.0233 AC: 81 AN: 3472

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5174

South Asian (SAS) AF: 0.00664 AC: 32 AN: 4818

European-Finnish (FIN) AF: 0.0290 AC: 308 AN: 10614

Middle Eastern (MID) AF: 0.0306 AC: 9 AN: 294

European-Non Finnish (NFE) AF: 0.0264 AC: 1798 AN: 68022

Other (OTH) AF: 0.0251 AC: 53 AN: 2112

Alfa AF: 0.0234 Hom.: 65

Bravo AF: 0.0162

Asia WGS AF: 0.00375 AC: 13 AN: 3478

EpiCase AF: 0.0261

EpiControl AF: 0.0266

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	-	3	not specified (3)
-	-	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	-0.81
CADD	Benign	5.6
DANN	Benign	0.86
PhyloP100		-3.1
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.090		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: rs5739; hg19: chr16-23203690;