chr16-23375747-C-G

Variant names:

• chr16-23375747-C-G
• rs61729788
• NM_000336.3:c.1162C>G

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_000336.3(SCNN1B):​c.1162C>G​(p.Arg388Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000124 in 1,613,288 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. 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 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: SCNN1B NM_000336.3 missense
• Clinical Significance: Not reported in ClinVar
• 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: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

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>G	p.Arg388Gly	missense	Exon 8 of 13	NP_000327.2	B2R812
	SCNN1B	NM_001410900.1		c.1054C>G	p.Arg352Gly	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>G	p.Arg388Gly	missense	Exon 8 of 13	ENSP00000345751.2	P51168-1
	SCNN1B	ENST00000307331.9	TSL:5	c.1297C>G	p.Arg433Gly	missense	Exon 9 of 14	ENSP00000302874.5	P51168-2
	SCNN1B	ENST00000962247.1		c.1258C>G	p.Arg420Gly	missense	Exon 8 of 13	ENSP00000632306.1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152190 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461098 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 726906

African (AFR) AF: 0.0000299 AC: 1 AN: 33444

American (AMR) AF: 0.00 AC: 0 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: 0.00 AC: 0 AN: 86242

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53416

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111320

Other (OTH) AF: 0.00 AC: 0 AN: 60362

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152190 Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1 AN XY: 74364

African (AFR) AF: 0.0000241 AC: 1 AN: 41436

American (AMR) AF: 0.00 AC: 0 AN: 15284

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5196

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

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

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68028

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.00 Hom.: 23

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.38
BayesDel_addAF	Benign	-0.0097	T
BayesDel_noAF	Benign	-0.25
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.60	D
Eigen	Benign	0.056
Eigen_PC	Benign	0.17
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.88	D
M_CAP	Benign	0.030	D
MetaRNN	Uncertain	0.65	D
MetaSVM	Benign	-0.59	T
MutationAssessor	Uncertain	2.9	M
PhyloP100		2.4
PrimateAI	Benign	0.22	T
PROVEAN	Uncertain	-3.9	D
REVEL	Uncertain	0.32
Sift	Benign	0.10	T
Sift4G	Uncertain	0.015	D
Polyphen		0.0	B
Vest4		0.57
MutPred		0.70		Loss of catalytic residue at R388 (P = 0.0621)
MVP		0.82
MPC		0.19
ClinPred		0.97	D
GERP RS		4.7
Varity_R		0.56
gMVP		0.61
Mutation Taster		=78/22	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: rs61729788; hg19: chr16-23387068;