16-23380643-G-A

Variant names:

• chr16-23380643-G-A
• rs61759926
• NM_000336.3:c.1765G>A

Variant summary

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

The NM_000336.3(SCNN1B):​c.1765G>A​(p.Gly589Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00253 in 1,613,440 control chromosomes in the GnomAD database, including 9 homozygotes. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0018 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0026 (9 hom.)
• Consequence: SCNN1B NM_000336.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 0.388
• Publications: 9 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, Labcorp Genetics (formerly Invitae)
• pseudohypoaldosteronism, type IB2, autosomal recessive

  Inheritance: AR Classification: DEFINITIVE Submitted by: Ambry Genetics
• bronchiectasis with or without elevated sweat chloride 1

  Inheritance: AD, SD Classification: STRONG, LIMITED Submitted by: PanelApp Australia, Ambry Genetics
• pseudohypoaldosteronism, type IB1, autosomal recessive

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

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

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

• BP4: Computational evidence support a benign effect (MetaRNN=0.009487271).
• BP6: Variant 16-23380643-G-A is Benign according to our data. Variant chr16-23380643-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 165171.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00177 (270/152342) while in subpopulation NFE AF = 0.00251 (171/68024). AF 95% confidence interval is 0.00221. There are 0 homozygotes in GnomAd4. There are 129 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 9 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SCNN1B	NM_000336.3	MANE Select	c.1765G>A	p.Gly589Ser	missense	Exon 13 of 13	NP_000327.2
	SCNN1B	NM_001410900.1		c.1657G>A	p.Gly553Ser	missense	Exon 12 of 12	NP_001397829.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SCNN1B	ENST00000343070.7	TSL:1 MANE Select	c.1765G>A	p.Gly589Ser	missense	Exon 13 of 13	ENSP00000345751.2
	SCNN1B	ENST00000307331.9	TSL:5	c.1900G>A	p.Gly634Ser	missense	Exon 14 of 14	ENSP00000302874.5
	SCNN1B	ENST00000568923.5	TSL:3	c.1684G>A	p.Gly562Ser	missense	Exon 12 of 12	ENSP00000456309.1

Frequencies

GnomAD3 genomes AF: 0.00177 AC: 270 AN: 152224 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000675

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000458

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00565

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00251

Gnomad OTH AF: 0.00191

GnomAD2 exomes AF: 0.00189 AC: 470 AN: 249136 AF XY: 0.00187

Gnomad AFR exome AF: 0.000377

Gnomad AMR exome AF: 0.000609

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00688

Gnomad NFE exome AF: 0.00240

Gnomad OTH exome AF: 0.00197

GnomAD4 exome AF: 0.00261 AC: 3816 AN: 1461098 Hom.: 9 Cov.: 32 AF XY: 0.00249 AC XY: 1811 AN XY: 726842

African (AFR) AF: 0.000269 AC: 9 AN: 33470

American (AMR) AF: 0.000671 AC: 30 AN: 44684

Ashkenazi Jewish (ASJ) AF: 0.0000383 AC: 1 AN: 26090

East Asian (EAS) AF: 0.00 AC: 0 AN: 39688

South Asian (SAS) AF: 0.000383 AC: 33 AN: 86204

European-Finnish (FIN) AF: 0.00748 AC: 398 AN: 53180

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5714

European-Non Finnish (NFE) AF: 0.00290 AC: 3221 AN: 1111706

Other (OTH) AF: 0.00205 AC: 124 AN: 60362

GnomAD4 genome AF: 0.00177 AC: 270 AN: 152342 Hom.: 0 Cov.: 33 AF XY: 0.00173 AC XY: 129 AN XY: 74476

African (AFR) AF: 0.000673 AC: 28 AN: 41590

American (AMR) AF: 0.000457 AC: 7 AN: 15312

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5170

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00565 AC: 60 AN: 10624

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00251 AC: 171 AN: 68024

Other (OTH) AF: 0.00189 AC: 4 AN: 2114

Alfa AF: 0.00182 Hom.: 0

Bravo AF: 0.00134

TwinsUK AF: 0.00189 AC: 7

ALSPAC AF: 0.00337 AC: 13

ESP6500AA AF: 0.000683 AC: 3

ESP6500EA AF: 0.00221 AC: 19

ExAC AF: 0.00198 AC: 240

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.00202

EpiControl AF: 0.00231

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Bronchiectasis with or without elevated sweat chloride 1 (1)
-	-	1	Bronchiectasis with or without elevated sweat chloride 1;C5774176:Pseudohypoaldosteronism, type IB1, autosomal recessive;CN031472:Liddle syndrome 1 (1)
-	-	1	Liddle syndrome 1 (1)
-	-	1	not provided (1)
-	-	1	not specified (1)
-	-	1	Pseudohypoaldosteronism, type IB1, autosomal recessive (1)
-	-	1	SCNN1B-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.075
BayesDel_addAF	Benign	-0.45	T
BayesDel_noAF	Benign	-0.42
CADD	Benign	1.0
DANN	Benign	0.89
DEOGEN2	Benign	0.16	T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.36	N
LIST_S2	Benign	0.77	T
M_CAP	Benign	0.031	D
MetaRNN	Benign	0.0095	T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	1.5	L
PhyloP100		0.39
PrimateAI	Benign	0.30	T
PROVEAN	Benign	-0.51	N
REVEL	Benign	0.19
Sift	Benign	0.42	T
Sift4G	Benign	0.071	T
Polyphen		0.15	B
Vest4		0.074
MVP		0.59
MPC		0.17
ClinPred		0.0011	T
GERP RS		1.4
Varity_R		0.034
gMVP		0.64
Mutation Taster		=93/7	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: rs61759926; hg19: chr16-23391964;