chr16-23189642-G-C

Position:

• chr16-23189642-G-C

Variant summary

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

The NM_001039.4(SCNN1G):​c.589G>C​(p.Glu197Gln) 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. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E197K) has been classified as Benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: SCNN1G NM_001039.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:2
• Conservation: PhyloP100: 0.886

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.09678075).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SCNN1G	NM_001039.4	c.589G>C	p.Glu197Gln	missense_variant	3/13	ENST00000300061.3	NP_001030.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SCNN1G	ENST00000300061.3	c.589G>C	p.Glu197Gln	missense_variant	3/13	1	NM_001039.4	ENSP00000300061.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, single submitter

Submissions by phenotype

Pseudohypoaldosteronism, type IB1, autosomal recessive Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

Liddle syndrome 2 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.084
BayesDel_addAF	Benign	-0.14	T
BayesDel_noAF	Benign	-0.43
CADD	Benign	10
DANN	Benign	0.96
DEOGEN2	Benign	0.20	T
Eigen	Benign	-0.79
Eigen_PC	Benign	-0.73
FATHMM_MKL	Benign	0.17	N
LIST_S2	Benign	0.51	T
M_CAP	Benign	0.013	T
MetaRNN	Benign	0.097	T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	0.77	N
PrimateAI	Benign	0.32	T
PROVEAN	Benign	-1.1	N
REVEL	Benign	0.030
Sift	Benign	0.15	T
Sift4G	Benign	0.23	T
Polyphen		0.0070	B
Vest4		0.081
MutPred		0.42		Loss of sheet (P = 0.0357);
MVP		0.59
MPC		0.22
ClinPred		0.085	T
GERP RS		2.8
Varity_R		0.077
gMVP		0.46

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: rs5738; hg19: chr16-23200963;