rs5736

Variant names:

• chr16-23189600-G-A
• rs5736
• NM_001039.4:c.547G>A

Your query was ambiguous. Multiple possible variants found:

• chr16-23189600-G-A
• chr16-23189600-G-T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001039.4(SCNN1G):​c.547G>A​(p.Gly183Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0029 in 1,614,194 control chromosomes in the GnomAD database, including 73 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. G183G) has been classified as Benign.

• Frequency:
  • Genomes: 𝑓 0.011 (29 hom., cov: 32)
  • Exomes 𝑓: 0.0020 (44 hom.)
• Consequence: SCNN1G NM_001039.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts P:1 B:10
• Conservation: PhyloP100: 1.76
• Publications: 24 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 (MetaRNN=0.06252736).
• BP6: Variant 16-23189600-G-A is Benign according to our data. Variant chr16-23189600-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 8828.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0114 (1738/152316) while in subpopulation AFR AF = 0.0365 (1519/41570). AF 95% confidence interval is 0.035. There are 29 homozygotes in GnomAd4. There are 838 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 29 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SCNN1G	NM_001039.4	MANE Select	c.547G>A	p.Gly183Ser	missense	Exon 3 of 13	NP_001030.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SCNN1G	ENST00000300061.3	TSL:1 MANE Select	c.547G>A	p.Gly183Ser	missense	Exon 3 of 13	ENSP00000300061.2

Frequencies

GnomAD3 genomes AF: 0.0114 AC: 1734 AN: 152198 Hom.: 29 Cov.: 32

Gnomad AFR AF: 0.0365

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00530

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0106

Gnomad SAS AF: 0.00186

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.000852

Gnomad OTH AF: 0.00622

GnomAD2 exomes AF: 0.00409 AC: 1028 AN: 251488 AF XY: 0.00325

Gnomad AFR exome AF: 0.0373

Gnomad AMR exome AF: 0.00304

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0101

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000712

Gnomad OTH exome AF: 0.00456

GnomAD4 exome AF: 0.00201 AC: 2940 AN: 1461878 Hom.: 44 Cov.: 34 AF XY: 0.00188 AC XY: 1366 AN XY: 727240

African (AFR) AF: 0.0374 AC: 1251 AN: 33480

American (AMR) AF: 0.00335 AC: 150 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.0116 AC: 462 AN: 39700

South Asian (SAS) AF: 0.000858 AC: 74 AN: 86258

European-Finnish (FIN) AF: 0.0000187 AC: 1 AN: 53418

Middle Eastern (MID) AF: 0.0116 AC: 67 AN: 5768

European-Non Finnish (NFE) AF: 0.000560 AC: 623 AN: 1111998

Other (OTH) AF: 0.00517 AC: 312 AN: 60396

GnomAD4 genome AF: 0.0114 AC: 1738 AN: 152316 Hom.: 29 Cov.: 32 AF XY: 0.0113 AC XY: 838 AN XY: 74476

African (AFR) AF: 0.0365 AC: 1519 AN: 41570

American (AMR) AF: 0.00529 AC: 81 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.0106 AC: 55 AN: 5182

South Asian (SAS) AF: 0.00186 AC: 9 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

Middle Eastern (MID) AF: 0.0102 AC: 3 AN: 294

European-Non Finnish (NFE) AF: 0.000853 AC: 58 AN: 68030

Other (OTH) AF: 0.00616 AC: 13 AN: 2112

Alfa AF: 0.00537 Hom.: 89

Bravo AF: 0.0131

TwinsUK AF: 0.000809 AC: 3

ALSPAC AF: 0.00104 AC: 4

ESP6500AA AF: 0.0357 AC: 157

ESP6500EA AF: 0.000930 AC: 8

ExAC AF: 0.00475 AC: 577

Asia WGS AF: 0.0100 AC: 36 AN: 3478

EpiCase AF: 0.000927

EpiControl AF: 0.00119

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not provided (5)
-	-	2	Pseudohypoaldosteronism, type IB1, autosomal recessive (2)
1	-	-	Bronchiectasis with or without elevated sweat chloride 3 (1)
-	-	1	Liddle syndrome 2 (1)
-	-	1	not specified (1)
-	-	1	SCNN1G-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.057
BayesDel_addAF	Benign	-0.51	T
BayesDel_noAF	Benign	-0.48
CADD	Benign	2.0
DANN	Benign	0.33
DEOGEN2	Benign	0.084	T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.011	N
LIST_S2	Benign	0.54	T
MetaRNN	Benign	0.063	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-1.4	N
PhyloP100		1.8
PrimateAI	Benign	0.28	T
PROVEAN	Benign	0.92	N
REVEL	Benign	0.14
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.0010	B
Vest4		0.083
MVP		0.39
MPC		0.21
ClinPred		0.00072	T
GERP RS		3.5
Varity_R		0.018
gMVP		0.28
Mutation Taster		=99/1	polymorphism

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: rs5736; hg19: chr16-23200921; COSMIC: COSV55602237;