16-23348675-C-A

Position:

• chr16-23348675-C-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_000336.3(SCNN1B):​c.76C>A​(p.Leu26Met) 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. 12/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 31)
• Consequence: SCNN1B NM_000336.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.39

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 Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.24623048).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SCNN1B	NM_000336.3	c.76C>A	p.Leu26Met	missense_variant	2/13	ENST00000343070.7	NP_000327.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SCNN1B	ENST00000343070.7	c.76C>A	p.Leu26Met	missense_variant	2/13	1	NM_000336.3	ENSP00000345751.2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Bronchiectasis with or without elevated sweat chloride 1;C5774255:Pseudohypoaldosteronism, type IB2, autosomal recessive;CN031472:Liddle syndrome 1 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Feb 19, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.21
BayesDel_addAF	Uncertain	0.020	T
BayesDel_noAF	Benign	-0.21
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Benign	0.19	T;.;.;.
Eigen	Benign	0.18
Eigen_PC	Benign	0.20
FATHMM_MKL	Benign	0.68	D
LIST_S2	Benign	0.83	T;T;T;T
M_CAP	Benign	0.033	D
MetaRNN	Benign	0.25	T;T;T;T
MetaSVM	Benign	-0.68	T
MutationAssessor	Benign	0.77	N;.;.;.
PrimateAI	Uncertain	0.73	T
PROVEAN	Benign	0.39	N;N;N;N
REVEL	Uncertain	0.38
Sift	Benign	1.0	T;T;T;T
Sift4G	Benign	0.091	T;T;T;T
Polyphen		1.0	D;.;.;.
Vest4		0.33
MutPred		0.49		Gain of methylation at K23 (P = 0.0675);.;Gain of methylation at K23 (P = 0.0675);Gain of methylation at K23 (P = 0.0675);
MVP		0.79
MPC		0.62
ClinPred		0.58	D
GERP RS		4.0
Varity_R		0.18
gMVP		0.85

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: rs1464718244; hg19: chr16-23359996;