NM_000336.3:c.1781C>T

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_000336.3(SCNN1B):c.1781C>T(p.Thr594Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00157 in 1,612,722 control chromosomes in the GnomAD database, including 31 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 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. T594T) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0083 ( 12 hom., cov: 32)

Exomes 𝑓: 0.00087 ( 19 hom. )

Consequence

SCNN1B
NM_000336.3 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: -0.868

Publications

26 publications found

Variant links:

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

SCNN1B links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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

BP4

Computational evidence support a benign effect (MetaRNN=0.0025485158).

BP6

Variant 16-23380659-C-T is Benign according to our data. Variant chr16-23380659-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 666637.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 = 0.00833 (1269/152336) while in subpopulation AFR AF = 0.0289 (1201/41580). AF 95% confidence interval is 0.0275. There are 12 homozygotes in GnomAd4. There are 585 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 12 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.1781C>T	p.Thr594Met	missense	Exon 13 of 13	NP_000327.2	B2R812
	SCNN1B	NM_001410900.1		c.1673C>T	p.Thr558Met	missense	Exon 12 of 12	NP_001397829.1	H3BQ95

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
SCNN1B	ENST00000343070.7	TSL:1 MANE Select	c.1781C>T	p.Thr594Met	missense	Exon 13 of 13	ENSP00000345751.2	P51168-1
SCNN1B	ENST00000307331.9	TSL:5	c.1916C>T	p.Thr639Met	missense	Exon 14 of 14	ENSP00000302874.5	P51168-2
SCNN1B	ENST00000962247.1		c.1877C>T	p.Thr626Met	missense	Exon 13 of 13	ENSP00000632306.1

Frequencies

GnomAD3 genomes

AF:

0.00832

AC:

1266

AN:

152218

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0289

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00294

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000386

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00949

Gnomad NFE

AF:

0.000103

Gnomad OTH

AF:

0.00478

GnomAD2 exomes

AF:

0.00210

AC:

520

AN:

247544

AF XY:

0.00158

show subpopulations

Gnomad AFR exome

AF:

0.0293

Gnomad AMR exome

AF:

0.00122

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000110

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000117

Gnomad OTH exome

AF:

0.000331

GnomAD4 exome

AF:

0.000866

AC:

1264

AN:

1460386

Hom.:

Cov.:

AF XY:

0.000767

AC XY:

557

AN XY:

726426

show subpopulations

African (AFR)

AF:

0.0301

AC:

1007

AN:

33464

American (AMR)

AF:

0.00137

AC:

AN:

44666

Ashkenazi Jewish (ASJ)

AF:

0.0000384

AC:

AN:

26072

East Asian (EAS)

AF:

0.000706

AC:

AN:

39682

South Asian (SAS)

AF:

0.000232

AC:

AN:

86184

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52870

Middle Eastern (MID)

AF:

0.00107

AC:

AN:

5630

European-Non Finnish (NFE)

AF:

0.0000486

AC:

AN:

1111490

Other (OTH)

AF:

0.00144

AC:

AN:

60328

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.481

Heterozygous variant carriers

160

239

319

399

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

128

160

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00833

AC:

1269

AN:

152336

Hom.:

Cov.:

AF XY:

0.00785

AC XY:

585

AN XY:

74476

show subpopulations

African (AFR)

AF:

0.0289

AC:

1201

AN:

41580

American (AMR)

AF:

0.00294

AC:

AN:

15312

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.000387

AC:

AN:

5170

South Asian (SAS)

AF:

0.000207

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10624

Middle Eastern (MID)

AF:

0.0102

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000103

AC:

AN:

68030

Other (OTH)

AF:

0.00473

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

135

203

270

338

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00290

Hom.:

Bravo

AF:

0.00972

ESP6500AA

AF:

0.0303

AC:

133

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.00259

AC:

314

Asia WGS

AF:

0.00115

AC:

AN:

3478

EpiCase

AF:

0.000109

EpiControl

AF:

0.00

ClinVar

ClinVar submissions

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (3)

not specified (2)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.074

BayesDel_addAF

Benign

-0.51

BayesDel_noAF

Benign

-0.48

CADD

Benign

(source)

DANN

Uncertain

0.97

DEOGEN2

Benign

0.24

Eigen

Benign

-0.92

Eigen_PC

Benign

-1.0

FATHMM_MKL

Benign

0.0094

LIST_S2

Benign

0.44

MetaRNN

Benign

0.0025

MetaSVM

Benign

-0.85

MutationAssessor

Benign

1.8

PhyloP100

-0.87

PrimateAI

Benign

0.28

PROVEAN

Benign

-0.91

REVEL

Benign

0.23

Sift

Benign

0.066

Sift4G

Benign

0.11

Polyphen

0.83

Vest4

0.084

MVP

0.74

MPC

0.15

ClinPred

0.0046

GERP RS

-4.9

Varity_R

0.017

gMVP

0.47

Mutation Taster

=100/0

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over