16-23375747-C-T

Variant names:

• chr16-23375747-C-T
• rs61729788
• NM_000336.3:c.1162C>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_000336.3(SCNN1B):​c.1162C>T​(p.Arg388Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00217 in 1,613,382 control chromosomes in the GnomAD database, including 46 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R388H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0096 (19 hom., cov: 32)
  • Exomes 𝑓: 0.0014 (27 hom.)
• Consequence: SCNN1B NM_000336.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 2.39
• Publications: 5 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
• pseudohypoaldosteronism, type IB1, autosomal recessive

  Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet
• bronchiectasis with or without elevated sweat chloride 1

  Inheritance: SD, AD Classification: STRONG, LIMITED Submitted by: Ambry Genetics, PanelApp Australia
• 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=0.011910081).
• BP6: Variant 16-23375747-C-T is Benign according to our data. Variant chr16-23375747-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 318432.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 = 0.00959 (1460/152304) while in subpopulation AFR AF = 0.0327 (1357/41554). AF 95% confidence interval is 0.0312. There are 19 homozygotes in GnomAd4. There are 672 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 19 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.1162C>T	p.Arg388Cys	missense	Exon 8 of 13	NP_000327.2	B2R812
	SCNN1B	NM_001410900.1		c.1054C>T	p.Arg352Cys	missense	Exon 7 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.1162C>T	p.Arg388Cys	missense	Exon 8 of 13	ENSP00000345751.2	P51168-1
	SCNN1B	ENST00000307331.9	TSL:5	c.1297C>T	p.Arg433Cys	missense	Exon 9 of 14	ENSP00000302874.5	P51168-2
	SCNN1B	ENST00000962247.1		c.1258C>T	p.Arg420Cys	missense	Exon 8 of 13	ENSP00000632306.1

Frequencies

GnomAD3 genomes AF: 0.00956 AC: 1455 AN: 152186 Hom.: 19 Cov.: 32

Gnomad AFR AF: 0.0326

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00399

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000426

Gnomad OTH AF: 0.00526

GnomAD2 exomes AF: 0.00271 AC: 681 AN: 251494 AF XY: 0.00197

Gnomad AFR exome AF: 0.0331

Gnomad AMR exome AF: 0.00168

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000462

Gnomad NFE exome AF: 0.000659

Gnomad OTH exome AF: 0.000977

GnomAD4 exome AF: 0.00140 AC: 2049 AN: 1461078 Hom.: 27 Cov.: 31 AF XY: 0.00122 AC XY: 890 AN XY: 726898

African (AFR) AF: 0.0324 AC: 1083 AN: 33430

American (AMR) AF: 0.00195 AC: 87 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39692

South Asian (SAS) AF: 0.000128 AC: 11 AN: 86242

European-Finnish (FIN) AF: 0.0000187 AC: 1 AN: 53416

Middle Eastern (MID) AF: 0.000520 AC: 3 AN: 5766

European-Non Finnish (NFE) AF: 0.000660 AC: 734 AN: 1111314

Other (OTH) AF: 0.00215 AC: 130 AN: 60362

GnomAD4 genome AF: 0.00959 AC: 1460 AN: 152304 Hom.: 19 Cov.: 32 AF XY: 0.00902 AC XY: 672 AN XY: 74492

African (AFR) AF: 0.0327 AC: 1357 AN: 41554

American (AMR) AF: 0.00399 AC: 61 AN: 15304

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.000414 AC: 2 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10626

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

European-Non Finnish (NFE) AF: 0.000426 AC: 29 AN: 68020

Other (OTH) AF: 0.00520 AC: 11 AN: 2114

Alfa AF: 0.00415 Hom.: 23

Bravo AF: 0.0114

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.0360 AC: 158

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.00337 AC: 409

Asia WGS AF: 0.00173 AC: 6 AN: 3478

EpiCase AF: 0.000818

EpiControl AF: 0.000474

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	-	1	Bronchiectasis with or without elevated sweat chloride 1 (1)
-	-	1	Liddle syndrome 1 (1)
-	-	1	Pseudohypoaldosteronism, type IB1, autosomal recessive (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.31
BayesDel_addAF	Benign	-0.38	T
BayesDel_noAF	Benign	-0.30
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.65	D
Eigen	Benign	0.086
Eigen_PC	Benign	0.19
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.87	D
MetaRNN	Benign	0.012	T
MetaSVM	Benign	-0.75	T
MutationAssessor	Uncertain	2.9	M
PhyloP100		2.4
PrimateAI	Benign	0.23	T
PROVEAN	Pathogenic	-4.7	D
REVEL	Benign	0.29
Sift	Benign	0.063	T
Sift4G	Uncertain	0.0020	D
Polyphen		0.0050	B
Vest4		0.39
MVP		0.82
MPC		0.21
ClinPred		0.046	T
GERP RS		4.7
Varity_R		0.31
gMVP		0.58
Mutation Taster		=80/20	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs61729788; hg19: chr16-23387068;