chr12-6346959-T-C

Position:

• chr12-6346959-T-C

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_001038.6(SCNN1A):​c.*914A>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00752 in 152,730 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0075 (4 hom., cov: 32)
  • Exomes 𝑓: 0.0088 (0 hom.)
• Consequence: SCNN1A NM_001038.6 3_prime_UTR
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:2
• Conservation: PhyloP100: 0.00400

Genes affected

SCNN1A (HGNC:10599): (sodium channel epithelial 1 subunit alpha) 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 alpha subunit, and mutations in this gene have been associated with pseudohypoaldosteronism type 1 (PHA1), a rare salt wasting disease resulting from target organ unresponsiveness to mineralocorticoids. Alternatively spliced transcript variants encoding different isoforms have been described for this gene. [provided by RefSeq, Apr 2009]

LOC112268088 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BP6: Variant 12-6346959-T-C is Benign according to our data. Variant chr12-6346959-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 310119.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1, Benign=1}.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00752 (1145/152278) while in subpopulation NFE AF= 0.0122 (833/68016). AF 95% confidence interval is 0.0116. There are 4 homozygotes in gnomad4. There are 535 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 4 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SCNN1A	NM_001038.6	c.*914A>G		3_prime_UTR_variant	13/13	ENST00000228916.7
LOC112268088	XR_002957396.2	n.808T>C		non_coding_transcript_exon_variant	2/2
SCNN1A	NM_001159575.2	c.*914A>G		3_prime_UTR_variant	13/13
SCNN1A	NM_001159576.2	c.*914A>G		3_prime_UTR_variant	12/12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SCNN1A	ENST00000228916.7	c.*914A>G		3_prime_UTR_variant	13/13	1	NM_001038.6	A2
SCNN1A	ENST00000360168.7	c.*914A>G		3_prime_UTR_variant	12/12	1		A2
SCNN1A	ENST00000540037.5	c.*914A>G		3_prime_UTR_variant	11/11	1

Frequencies

GnomAD3 genomes AF: 0.00752 AC: 1145 AN: 152160 Hom.: 4 Cov.: 32

Gnomad AFR AF: 0.00246

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00399

Gnomad ASJ AF: 0.00606

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00414

Gnomad FIN AF: 0.00962

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0122

Gnomad OTH AF: 0.00288

GnomAD4 exome AF: 0.00885 AC: 4 AN: 452 Hom.: 0 Cov.: 0 AF XY: 0.0112 AC XY: 3 AN XY: 268

Gnomad4 ASJ exome AF: 0.00

Gnomad4 FIN exome AF: 0.00939

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.00752 AC: 1145 AN: 152278 Hom.: 4 Cov.: 32 AF XY: 0.00719 AC XY: 535 AN XY: 74442

Gnomad4 AFR AF: 0.00245

Gnomad4 AMR AF: 0.00399

Gnomad4 ASJ AF: 0.00606

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00414

Gnomad4 FIN AF: 0.00962

Gnomad4 NFE AF: 0.0122

Gnomad4 OTH AF: 0.00285

Alfa AF: 0.0115 Hom.: 1

Bravo AF: 0.00688

Asia WGS AF: 0.000866 AC: 3 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Pseudohypoaldosteronism, type IB1, autosomal recessive Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Bronchiectasis with or without elevated sweat chloride 2 Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 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. -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

May 19, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	2.3
DANN	Benign	0.24
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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: rs62619209; hg19: chr12-6456125;