16-23380584-C-G

Variant names:

• chr16-23380584-C-G
• rs140927806
• NM_000336.3:c.1706C>G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_000336.3(SCNN1B):​c.1706C>G​(p.Ala569Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. 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. A569V) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 33)
• Consequence: SCNN1B NM_000336.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.15
• Publications: 6 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, 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

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.166341).

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.1706C>G	p.Ala569Gly	missense	Exon 13 of 13	NP_000327.2	B2R812
	SCNN1B	NM_001410900.1		c.1598C>G	p.Ala533Gly	missense	Exon 12 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.1706C>G	p.Ala569Gly	missense	Exon 13 of 13	ENSP00000345751.2	P51168-1
	SCNN1B	ENST00000307331.9	TSL:5	c.1841C>G	p.Ala614Gly	missense	Exon 14 of 14	ENSP00000302874.5	P51168-2
	SCNN1B	ENST00000962247.1		c.1802C>G	p.Ala601Gly	missense	Exon 13 of 13	ENSP00000632306.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 2

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.084
BayesDel_addAF	Benign	0.00012	T
BayesDel_noAF	Benign	-0.24
CADD	Benign	15
DANN	Uncertain	0.99
DEOGEN2	Benign	0.16	T
Eigen	Benign	-0.40
Eigen_PC	Benign	-0.33
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Benign	0.84	T
M_CAP	Uncertain	0.092	D
MetaRNN	Benign	0.17	T
MetaSVM	Benign	-0.59	T
MutationAssessor	Uncertain	2.7	M
PhyloP100		3.2
PrimateAI	Benign	0.44	T
PROVEAN	Benign	-0.82	N
REVEL	Benign	0.23
Sift	Benign	0.18	T
Sift4G	Benign	0.10	T
Polyphen		0.50	P
Vest4		0.18
MutPred		0.10		Loss of MoRF binding (P = 0.1366)
MVP		0.84
MPC		0.24
ClinPred		0.58	D
GERP RS		4.8
Varity_R		0.11
gMVP		0.59

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: rs140927806; hg19: chr16-23391905;