rs35731153

Variant names:

• chr16-23348844-C-G
• rs35731153
• NM_000336.3:c.245C>G

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_000336.3(SCNN1B):​c.245C>G​(p.Ser82Cys) variant causes a missense change. The variant allele was found at a frequency of 0.00718 in 1,614,162 control chromosomes in the GnomAD database, including 63 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in ClinVar. Synonymous variant affecting the same amino acid position (i.e. S82S) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0044 (3 hom., cov: 31)
  • Exomes 𝑓: 0.0075 (60 hom.)
• Consequence: SCNN1B NM_000336.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:1 B:14
• Conservation: PhyloP100: 5.83
• Publications: 17 publications found

Genes affected

SCNN1B (HGNC:10600): (sodium channel epithelial 1 subunit beta) 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 beta subunit, and mutations in this gene have been associated with pseudohypoaldosteronism type 1 (PHA1), and Liddle syndrome. [provided by RefSeq, Apr 2009]

SCNN1B Gene-Disease associations (from GenCC):

• Liddle syndrome 1

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, PanelApp Australia, Labcorp Genetics (formerly Invitae)
• pseudohypoaldosteronism, type IB2, autosomal recessive

  Inheritance: AR Classification: DEFINITIVE Submitted by: Ambry Genetics
• pseudohypoaldosteronism, type IB1, autosomal recessive

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

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• bronchiectasis with or without elevated sweat chloride 1

  Inheritance: SD Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.018293321).
• BP6: Variant 16-23348844-C-G is Benign according to our data. Variant chr16-23348844-C-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 8844.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00445 (677/152288) while in subpopulation NFE AF = 0.00685 (466/68034). AF 95% confidence interval is 0.00634. There are 3 homozygotes in GnomAd4. There are 304 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 3 AR,AD,SD gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000336.3. 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
	SCNN1B	NM_000336.3	MANE Select	c.245C>G	p.Ser82Cys	missense	Exon 2 of 13	NP_000327.2	B2R812
	SCNN1B	NM_001410900.1		c.245C>G	p.Ser82Cys	missense	Exon 2 of 12	NP_001397829.1	H3BQ95

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SCNN1B	ENST00000343070.7	TSL:1 MANE Select	c.245C>G	p.Ser82Cys	missense	Exon 2 of 13	ENSP00000345751.2	P51168-1
	SCNN1B	ENST00000307331.9	TSL:5	c.380C>G	p.Ser127Cys	missense	Exon 3 of 14	ENSP00000302874.5	P51168-2
	SCNN1B	ENST00000962247.1		c.245C>G	p.Ser82Cys	missense	Exon 2 of 13	ENSP00000632306.1

Frequencies

GnomAD3 genomes AF: 0.00446 AC: 679 AN: 152170 Hom.: 4 Cov.: 31

Gnomad AFR AF: 0.00164

Gnomad AMI AF: 0.00329

Gnomad AMR AF: 0.00281

Gnomad ASJ AF: 0.00951

Gnomad EAS AF: 0.00116

Gnomad SAS AF: 0.000829

Gnomad FIN AF: 0.00301

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.00685

Gnomad OTH AF: 0.0105

GnomAD2 exomes AF: 0.00476 AC: 1193 AN: 250642 AF XY: 0.00466

Gnomad AFR exome AF: 0.00117

Gnomad AMR exome AF: 0.00260

Gnomad ASJ exome AF: 0.00714

Gnomad EAS exome AF: 0.000707

Gnomad FIN exome AF: 0.00370

Gnomad NFE exome AF: 0.00710

Gnomad OTH exome AF: 0.00506

GnomAD4 exome AF: 0.00746 AC: 10905 AN: 1461874 Hom.: 60 Cov.: 32 AF XY: 0.00719 AC XY: 5230 AN XY: 727240

African (AFR) AF: 0.000986 AC: 33 AN: 33480

American (AMR) AF: 0.00255 AC: 114 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00700 AC: 183 AN: 26136

East Asian (EAS) AF: 0.000781 AC: 31 AN: 39700

South Asian (SAS) AF: 0.00308 AC: 266 AN: 86258

European-Finnish (FIN) AF: 0.00414 AC: 221 AN: 53420

Middle Eastern (MID) AF: 0.00260 AC: 15 AN: 5768

European-Non Finnish (NFE) AF: 0.00870 AC: 9675 AN: 1111994

Other (OTH) AF: 0.00608 AC: 367 AN: 60396

GnomAD4 genome AF: 0.00445 AC: 677 AN: 152288 Hom.: 3 Cov.: 31 AF XY: 0.00408 AC XY: 304 AN XY: 74464

African (AFR) AF: 0.00164 AC: 68 AN: 41568

American (AMR) AF: 0.00281 AC: 43 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.00951 AC: 33 AN: 3470

East Asian (EAS) AF: 0.00116 AC: 6 AN: 5158

South Asian (SAS) AF: 0.000830 AC: 4 AN: 4820

European-Finnish (FIN) AF: 0.00301 AC: 32 AN: 10622

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.00685 AC: 466 AN: 68034

Other (OTH) AF: 0.00947 AC: 20 AN: 2112

Alfa AF: 0.00644 Hom.: 0

Bravo AF: 0.00465

TwinsUK AF: 0.00971 AC: 36

ALSPAC AF: 0.00908 AC: 35

ESP6500AA AF: 0.00319 AC: 14

ESP6500EA AF: 0.00802 AC: 69

ExAC AF: 0.00479 AC: 581

Asia WGS AF: 0.00346 AC: 12 AN: 3478

EpiCase AF: 0.00687

EpiControl AF: 0.00652

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
1	1	3	Bronchiectasis with or without elevated sweat chloride 1 (5)
-	-	5	not provided (5)
-	-	2	Liddle syndrome 1 (2)
-	-	2	not specified (2)
-	-	1	Pseudohypoaldosteronism, type IB1, autosomal recessive (1)
-	-	1	SCNN1B-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.52
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Uncertain	0.040
CADD	Pathogenic	26
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.71	D
Eigen	Pathogenic	0.73
Eigen_PC	Pathogenic	0.69
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Uncertain	0.86	D
M_CAP	Benign	0.059	D
MetaRNN	Benign	0.018	T
MetaSVM	Uncertain	-0.13	T
MutationAssessor	Pathogenic	3.0	M
PhyloP100		5.8
PrimateAI	Uncertain	0.53	T
PROVEAN	Uncertain	-3.9	D
REVEL	Uncertain	0.53
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0060	D
Polyphen		1.0	D
Vest4		0.59
MVP		0.95
MPC		0.62
ClinPred		0.024	T
GERP RS		5.0
PromoterAI		-0.014	Neutral
Varity_R		0.56
gMVP		0.77
Mutation Taster		=94/6	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: rs35731153; hg19: chr16-23360165; COSMIC: COSV56305336;