12-6375543-T-C

Position:

• chr12-6375543-T-C

Variant summary

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

The NM_001038.6(SCNN1A):​c.-93A>G variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.567 in 1,533,478 control chromosomes in the GnomAD database, including 256,433 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.66 (35359 hom., cov: 30)
  • Exomes 𝑓: 0.56 (221074 hom.)
• Consequence: SCNN1A NM_001038.6 5_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.480

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]

LTBR (HGNC:6718): (lymphotoxin beta receptor) This gene encodes a member of the tumor necrosis factor receptor superfamily. The major ligands of this receptor include lymphotoxin alpha/beta and tumor necrosis factor ligand superfamily member 14. The encoded protein plays a role in signalling during the development of lymphoid and other organs, lipid metabolism, immune response, and programmed cell death. Activity of this receptor has also been linked to carcinogenesis. Alternatively spliced transcript variants encoding multiple isoforms have been observed. [provided by RefSeq, Aug 2012]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 12-6375543-T-C is Benign according to our data. Variant chr12-6375543-T-C is described in ClinVar as [Benign]. Clinvar id is 310159.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.9 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SCNN1A	NM_001038.6	c.-93A>G		5_prime_UTR_variant	1/13	ENST00000228916.7	NP_001029.1
LTBR	NM_001270987.2	c.-13T>C		5_prime_UTR_variant	1/10		NP_001257916.1
LTBR	NM_001414309.1	c.-13T>C		5_prime_UTR_variant	1/10		NP_001401238.1
SCNN1A	NM_001159575.2	c.16-706A>G		intron_variant			NP_001153047.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SCNN1A	ENST00000228916.7	c.-93A>G		5_prime_UTR_variant	1/13	1	NM_001038.6	ENSP00000228916	A2

Frequencies

GnomAD3 genomes AF: 0.659 AC: 99809 AN: 151560 Hom.: 35297 Cov.: 30

Gnomad AFR AF: 0.907

Gnomad AMI AF: 0.491

Gnomad AMR AF: 0.663

Gnomad ASJ AF: 0.312

Gnomad EAS AF: 0.855

Gnomad SAS AF: 0.679

Gnomad FIN AF: 0.637

Gnomad MID AF: 0.382

Gnomad NFE AF: 0.517

Gnomad OTH AF: 0.571

GnomAD3 exomes AF: 0.615 AC: 80071 AN: 130094 Hom.: 26259 AF XY: 0.607 AC XY: 43100 AN XY: 70988

Gnomad AFR exome AF: 0.922

Gnomad AMR exome AF: 0.717

Gnomad ASJ exome AF: 0.321

Gnomad EAS exome AF: 0.864

Gnomad SAS exome AF: 0.653

Gnomad FIN exome AF: 0.633

Gnomad NFE exome AF: 0.513

Gnomad OTH exome AF: 0.525

GnomAD4 exome AF: 0.557 AC: 769947 AN: 1381798 Hom.: 221074 Cov.: 68 AF XY: 0.557 AC XY: 380108 AN XY: 681844

Gnomad4 AFR exome AF: 0.922

Gnomad4 AMR exome AF: 0.707

Gnomad4 ASJ exome AF: 0.316

Gnomad4 EAS exome AF: 0.850

Gnomad4 SAS exome AF: 0.653

Gnomad4 FIN exome AF: 0.638

Gnomad4 NFE exome AF: 0.529

Gnomad4 OTH exome AF: 0.560

GnomAD4 genome AF: 0.659 AC: 99938 AN: 151680 Hom.: 35359 Cov.: 30 AF XY: 0.665 AC XY: 49275 AN XY: 74110

Gnomad4 AFR AF: 0.907

Gnomad4 AMR AF: 0.664

Gnomad4 ASJ AF: 0.312

Gnomad4 EAS AF: 0.856

Gnomad4 SAS AF: 0.679

Gnomad4 FIN AF: 0.637

Gnomad4 NFE AF: 0.517

Gnomad4 OTH AF: 0.571

Alfa AF: 0.536 Hom.: 4791

Bravo AF: 0.668

Asia WGS AF: 0.772 AC: 2684 AN: 3476

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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. -

Pseudohypoaldosteronism, type IB1, autosomal recessive 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

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	6.8
DANN	Benign	0.76

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs10849447; hg19: chr12-6484709;