rs5727

Variant names:

• chr16-23215737-G-A
• rs5727
• NM_001039.4:c.*268G>A

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.*268G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.196 in 540,078 control chromosomes in the GnomAD database, including 11,359 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.21 (3524 hom., cov: 32)
  • Exomes 𝑓: 0.19 (7835 hom.)
• Consequence: SCNN1G NM_001039.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.149
• 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: Ambry Genetics, Labcorp Genetics (formerly Invitae), Laboratory for Molecular Medicine
• pseudohypoaldosteronism, type IB1, autosomal recessive

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

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BP6: Variant 16-23215737-G-A is Benign according to our data. Variant chr16-23215737-G-A is described in ClinVar as Benign. ClinVar VariationId is 318365.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.242 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SCNN1G	NM_001039.4	c.*268G>A		3_prime_UTR_variant	Exon 13 of 13	ENST00000300061.3	NP_001030.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SCNN1G	ENST00000300061.3	c.*268G>A		3_prime_UTR_variant	Exon 13 of 13	1	NM_001039.4	ENSP00000300061.2

Frequencies

GnomAD3 genomes AF: 0.212 AC: 32179 AN: 152020 Hom.: 3515 Cov.: 32

Gnomad AFR AF: 0.246

Gnomad AMI AF: 0.198

Gnomad AMR AF: 0.163

Gnomad ASJ AF: 0.227

Gnomad EAS AF: 0.0615

Gnomad SAS AF: 0.0739

Gnomad FIN AF: 0.231

Gnomad MID AF: 0.190

Gnomad NFE AF: 0.220

Gnomad OTH AF: 0.207

GnomAD4 exome AF: 0.190 AC: 73755 AN: 387940 Hom.: 7835 Cov.: 3 AF XY: 0.183 AC XY: 37701 AN XY: 205770

African (AFR) AF: 0.250 AC: 2782 AN: 11122

American (AMR) AF: 0.129 AC: 2151 AN: 16622

Ashkenazi Jewish (ASJ) AF: 0.236 AC: 2786 AN: 11828

East Asian (EAS) AF: 0.0550 AC: 1384 AN: 25174

South Asian (SAS) AF: 0.0846 AC: 3769 AN: 44572

European-Finnish (FIN) AF: 0.227 AC: 5238 AN: 23068

Middle Eastern (MID) AF: 0.174 AC: 288 AN: 1652

European-Non Finnish (NFE) AF: 0.219 AC: 50813 AN: 231596

Other (OTH) AF: 0.204 AC: 4544 AN: 22306

GnomAD4 genome AF: 0.212 AC: 32217 AN: 152138 Hom.: 3524 Cov.: 32 AF XY: 0.208 AC XY: 15489 AN XY: 74368

African (AFR) AF: 0.246 AC: 10209 AN: 41502

American (AMR) AF: 0.163 AC: 2487 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.227 AC: 786 AN: 3470

East Asian (EAS) AF: 0.0612 AC: 317 AN: 5178

South Asian (SAS) AF: 0.0740 AC: 357 AN: 4824

European-Finnish (FIN) AF: 0.231 AC: 2444 AN: 10566

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

European-Non Finnish (NFE) AF: 0.220 AC: 14932 AN: 67982

Other (OTH) AF: 0.214 AC: 452 AN: 2114

Alfa AF: 0.221 Hom.: 782

Bravo AF: 0.207

Asia WGS AF: 0.110 AC: 382 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Nov 22, 2019

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Pseudohypoaldosteronism, type IB1, autosomal recessive Benign:1

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign. -

Liddle syndrome 2 Benign:1

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	5.0
DANN	Benign	0.48
PhyloP100		0.15
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: rs5727; hg19: chr16-23227058;