16-23186472-C-G

Position:

• chr16-23186472-C-G

Variant summary

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

The NM_001039.4(SCNN1G):​c.201C>G​(p.Ile67Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: SCNN1G NM_001039.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.958

Genes affected

SCNN1G (HGNC:10602): (sodium channel epithelial 1 subunit gamma) 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 gamma subunit, and mutations in this gene have been associated with Liddle syndrome. [provided by RefSeq, Apr 2009]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SCNN1G	NM_001039.4	c.201C>G	p.Ile67Met	missense_variant	2/13	ENST00000300061.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SCNN1G	ENST00000300061.3	c.201C>G	p.Ile67Met	missense_variant	2/13	1	NM_001039.4	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Bronchiectasis with or without elevated sweat chloride 3 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Johns Hopkins Genomics, Johns Hopkins University

Dec 05, 2022

This SCNN1G missense variant is absent from a large population dataset and has not been reported in ClinVar nor the literature, to our knowledge. Two bioinformatic tools queried predict that this substitution would be damaging, but these algorithms have low specificity, especially for predicting gain of function or dominant negative variants. The isoleucine residue at this position is evolutionarily conserved across most of the species assessed. We consider the clinical significance of c.201C>G; p.Ile67Met in SCNN1G to be uncertain at this time. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.30
BayesDel_addAF	Benign	0.0099	T
BayesDel_noAF	Benign	-0.22
CADD	Benign	4.6
DANN	Benign	0.49
DEOGEN2	Benign	0.10	T
Eigen	Benign	-1.0
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.037	N
LIST_S2	Benign	0.84	T
M_CAP	Benign	0.028	D
MetaRNN	Uncertain	0.71	D
MetaSVM	Benign	-0.84	T
MutationAssessor	Benign	0.96	L
MutationTaster	Benign	0.99	N
PrimateAI	Uncertain	0.65	T
PROVEAN	Benign	0.39	N
REVEL	Uncertain	0.41
Sift	Benign	0.34	T
Sift4G	Uncertain	0.0070	D
Polyphen		0.94	P
Vest4		0.60
MutPred		0.66		Loss of stability (P = 0.1488);
MVP		0.42
MPC		2.3
ClinPred		0.41	T
GERP RS		-4.7
Varity_R		0.060
gMVP		0.90

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr16-23197793;