16-23380643-G-A

Position:

• chr16-23380643-G-A

Variant summary

Our verdict is Benign. Variant got -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. 16/21 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

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]

ACMG classification

Verdict is Benign. Variant got -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 [Likely_benign]. Clinvar id is 165171.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-23380643-G-A is described in Lovd as [Likely_benign].
• 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 male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome4 at 9 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SCNN1B	NM_000336.3	c.1765G>A	p.Gly589Ser	missense_variant	13/13	ENST00000343070.7	NP_000327.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SCNN1B	ENST00000343070.7	c.1765G>A	p.Gly589Ser	missense_variant	13/13	1	NM_000336.3	ENSP00000345751.2

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

GnomAD3 exomes AF: 0.00189 AC: 470 AN: 249136 Hom.: 2 AF XY: 0.00187 AC XY: 252 AN XY: 134964

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 SAS exome AF: 0.000426

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

Gnomad4 AFR exome AF: 0.000269

Gnomad4 AMR exome AF: 0.000671

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000383

Gnomad4 FIN exome AF: 0.00748

Gnomad4 NFE exome AF: 0.00290

Gnomad4 OTH exome AF: 0.00205

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

Gnomad4 AFR AF: 0.000673

Gnomad4 AMR AF: 0.000457

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00565

Gnomad4 NFE AF: 0.00251

Gnomad4 OTH AF: 0.00189

Alfa AF: 0.00188 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

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Jul 01, 2014

Gly589Ser in exon 13 of SCNN1B: This variant is not expected to have clinical si gnificance due to a lack of evolutionary conservation of the affected amino acid . Of note, 10 mammals carry a serine (Ser) at this position. Additionally, this variant has been identified in 19/8596 European American chromosomes and 3/4392 African American chromosomes by the NHLBI Exome Sequencing Project (http://evs. gs.washington.edu/EVS/; dbSNP rs61759926). -

Bronchiectasis with or without elevated sweat chloride 1;C5774176:Pseudohypoaldosteronism, type IB1, autosomal recessive;CN031472:Liddle syndrome 1 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Nov 12, 2021

- -

Pseudohypoaldosteronism, type IB1, autosomal recessive Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

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). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Oct 11, 2023

- -

SCNN1B-related disorder Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

May 24, 2023

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Liddle syndrome 1 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

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). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Bronchiectasis with or without elevated sweat chloride 1 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

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). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Computational scores

Source: dbNSFP v4.3

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;T;T;T
M_CAP	Benign	0.031	D
MetaRNN	Benign	0.0095	T;T;T;T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	1.5	L;.;.;.
PrimateAI	Benign	0.30	T
PROVEAN	Benign	-0.51	N;N;N;N
REVEL	Benign	0.19
Sift	Benign	0.42	T;T;T;T
Sift4G	Benign	0.071	T;T;T;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

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

Publications

LitVar

Other links and lift over

dbSNP: rs61759926; hg19: chr16-23391964;