12-6347869-C-T

Variant names:

• chr12-6347869-C-T
• rs557017986
• NM_001038.6:c.*4G>A

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Strong BP6_Moderate

The NM_001038.6(SCNN1A):​c.*4G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00021 in 1,599,986 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.00014 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00022 (0 hom.)
• Consequence: SCNN1A NM_001038.6 3_prime_UTR
• Clinical Significance: Likely benign criteria provided, single submitter B:2
• Conservation: PhyloP100: -0.513

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]

ACMG classification

Our verdict: Likely_benign. The variant received -6 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BP6: Variant 12-6347869-C-T is Benign according to our data. Variant chr12-6347869-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 310130.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SCNN1A	NM_001038.6	c.*4G>A		3_prime_UTR_variant	Exon 13 of 13	ENST00000228916.7	NP_001029.1
SCNN1A	NM_001159576.2	c.*4G>A		3_prime_UTR_variant	Exon 12 of 12		NP_001153048.1
SCNN1A	NM_001159575.2	c.*4G>A		3_prime_UTR_variant	Exon 13 of 13		NP_001153047.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SCNN1A	ENST00000228916	c.*4G>A		3_prime_UTR_variant	Exon 13 of 13	1	NM_001038.6	ENSP00000228916.2

Frequencies

GnomAD3 genomes AF: 0.000145 AC: 22 AN: 152240 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000482

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: 0.00316

Gnomad NFE AF: 0.000279

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000101 AC: 23 AN: 226842 AF XY: 0.000121

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000220

Gnomad OTH exome AF: 0.000177

GnomAD4 exome AF: 0.000217 AC: 314 AN: 1447628 Hom.: 0 Cov.: 28 AF XY: 0.000216 AC XY: 155 AN XY: 719224

Gnomad4 AFR exome AF: 0.00 AC: 0 AN: 33244

Gnomad4 AMR exome AF: 0.00 AC: 0 AN: 43560

Gnomad4 ASJ exome AF: 0.00 AC: 0 AN: 25814

Gnomad4 EAS exome AF: 0.00 AC: 0 AN: 39536

Gnomad4 SAS exome AF: 0.0000118 AC: 1 AN: 84400

Gnomad4 FIN exome AF: 0.00 AC: 0 AN: 51692

Gnomad4 NFE exome AF: 0.000279 AC: 308 AN: 1105284

Gnomad4 Remaining exome AF: 0.0000670 AC: 4 AN: 59746

GnomAD4 genome AF: 0.000144 AC: 22 AN: 152358 Hom.: 0 Cov.: 33 AF XY: 0.000107 AC XY: 8 AN XY: 74494

Gnomad4 AFR AF: 0.0000481 AC: 0.0000480931 AN: 0.0000480931

Gnomad4 AMR AF: 0.00 AC: 0 AN: 0

Gnomad4 ASJ AF: 0.00 AC: 0 AN: 0

Gnomad4 EAS AF: 0.00 AC: 0 AN: 0

Gnomad4 SAS AF: 0.00 AC: 0 AN: 0

Gnomad4 FIN AF: 0.00 AC: 0 AN: 0

Gnomad4 NFE AF: 0.000279 AC: 0.000279272 AN: 0.000279272

Gnomad4 OTH AF: 0.00 AC: 0 AN: 0

Alfa AF: 0.000179 Hom.: 0

Bravo AF: 0.000162

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, single submitter

Submissions by phenotype

Bronchiectasis with or without elevated sweat chloride 2 Benign:1

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Pseudohypoaldosteronism, type IB1, autosomal recessive Benign:1

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	0.61
DANN	Benign	0.57
Mutation Taster		=100/0	polymorphism

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: rs557017986; hg19: chr12-6457035;