chr16-23186404-G-A

Variant names:

• chr16-23186404-G-A
• rs1392208138
• NM_001039.4:c.133G>A

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_001039.4(SCNN1G):​c.133G>A​(p.Val45Met) variant causes a missense change. The variant allele was found at a frequency of 0.00000657 in 152,256 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
• Consequence: SCNN1G NM_001039.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.67

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]

ENSG00000285613 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.759

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SCNN1G	NM_001039.4	c.133G>A	p.Val45Met	missense_variant	Exon 2 of 13	ENST00000300061.3	NP_001030.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SCNN1G	ENST00000300061.3	c.133G>A	p.Val45Met	missense_variant	Exon 2 of 13	1	NM_001039.4	ENSP00000300061.2
ENSG00000285613	ENST00000648673.1	n.-9C>T		upstream_gene_variant

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152256 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 Cov.: 33

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152256 Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1 AN XY: 74384

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Bravo AF: 0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Bronchiectasis with or without elevated sweat chloride 3;C4748251:Liddle syndrome 2;C5774256:Pseudohypoaldosteronism, type IB3, autosomal recessive Uncertain:1

Apr 20, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.50
BayesDel_addAF	Uncertain	0.056	T
BayesDel_noAF	Benign	-0.16
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Benign	0.40	T
Eigen	Uncertain	0.53
Eigen_PC	Uncertain	0.41
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.90	D
M_CAP	Benign	0.063	D
MetaRNN	Pathogenic	0.76	D
MetaSVM	Uncertain	-0.094	T
MutationAssessor	Pathogenic	3.2	M
PrimateAI	Uncertain	0.73	T
PROVEAN	Benign	-1.9	N
REVEL	Uncertain	0.43
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.018	D
Polyphen		1.0	D
Vest4		0.62
MutPred		0.58		Gain of sheet (P = 0.0827);
MVP		0.78
MPC		2.4
ClinPred		0.97	D
GERP RS		4.5
Varity_R		0.28
gMVP		0.87

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: rs1392208138; hg19: chr16-23197725;