chr16-23186224-C-G

Position:

• chr16-23186224-C-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001039.4(SCNN1G):​c.-44-4C>G variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.23 in 1,593,792 control chromosomes in the GnomAD database, including 44,130 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.21 (3597 hom., cov: 32)
  • Exomes 𝑓: 0.23 (40533 hom.)
• Consequence: SCNN1G NM_001039.4 splice_region, splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.0004556
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.440

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]

(HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.78).
• BP6: Variant 16-23186224-C-G is Benign according to our data. Variant chr16-23186224-C-G is described in ClinVar as [Benign]. Clinvar id is 318343.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-23186224-C-G is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.299 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SCNN1G	NM_001039.4	c.-44-4C>G		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000300061.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SCNN1G	ENST00000300061.3	c.-44-4C>G		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_001039.4	P1
	ENST00000648673.1	n.172G>C		non_coding_transcript_exon_variant	1/4

Frequencies

GnomAD3 genomes AF: 0.207 AC: 31452 AN: 152050 Hom.: 3579 Cov.: 32

Gnomad AFR AF: 0.117

Gnomad AMI AF: 0.289

Gnomad AMR AF: 0.306

Gnomad ASJ AF: 0.246

Gnomad EAS AF: 0.159

Gnomad SAS AF: 0.220

Gnomad FIN AF: 0.239

Gnomad MID AF: 0.244

Gnomad NFE AF: 0.234

Gnomad OTH AF: 0.210

GnomAD3 exomes AF: 0.242 AC: 59816 AN: 247326 Hom.: 7765 AF XY: 0.237 AC XY: 31790 AN XY: 134148

Gnomad AFR exome AF: 0.117

Gnomad AMR exome AF: 0.393

Gnomad ASJ exome AF: 0.245

Gnomad EAS exome AF: 0.151

Gnomad SAS exome AF: 0.230

Gnomad FIN exome AF: 0.245

Gnomad NFE exome AF: 0.231

Gnomad OTH exome AF: 0.237

GnomAD4 exome AF: 0.233 AC: 335672 AN: 1441624 Hom.: 40533 Cov.: 28 AF XY: 0.233 AC XY: 167283 AN XY: 718428

Gnomad4 AFR exome AF: 0.114

Gnomad4 AMR exome AF: 0.389

Gnomad4 ASJ exome AF: 0.249

Gnomad4 EAS exome AF: 0.145

Gnomad4 SAS exome AF: 0.231

Gnomad4 FIN exome AF: 0.243

Gnomad4 NFE exome AF: 0.233

Gnomad4 OTH exome AF: 0.231

GnomAD4 genome AF: 0.207 AC: 31500 AN: 152168 Hom.: 3597 Cov.: 32 AF XY: 0.208 AC XY: 15466 AN XY: 74410

Gnomad4 AFR AF: 0.117

Gnomad4 AMR AF: 0.307

Gnomad4 ASJ AF: 0.246

Gnomad4 EAS AF: 0.159

Gnomad4 SAS AF: 0.222

Gnomad4 FIN AF: 0.239

Gnomad4 NFE AF: 0.234

Gnomad4 OTH AF: 0.209

Alfa AF: 0.166 Hom.: 489

Bravo AF: 0.211

Asia WGS AF: 0.193 AC: 668 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 12, 2018	- -

Pseudohypoaldosteronism, type IB1, autosomal recessive Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Liddle syndrome 2 Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.78
CADD	Benign	12
DANN	Benign	0.41

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00046
dbscSNV1_RF	Benign	0.0040
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: rs5731; hg19: chr16-23197545; COSMIC: COSV55597782;