chr12-6347240-C-A

Position:

• chr12-6347240-C-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001038.6(SCNN1A):​c.*633G>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.018 in 154,644 control chromosomes in the GnomAD database, including 30 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.018 (28 hom., cov: 32)
  • Exomes 𝑓: 0.022 (2 hom.)
• Consequence: SCNN1A NM_001038.6 3_prime_UTR
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.447

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

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP6: Variant 12-6347240-C-A is Benign according to our data. Variant chr12-6347240-C-A is described in ClinVar as [Likely_benign]. Clinvar id is 310122.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0179 (2725/152284) while in subpopulation NFE AF= 0.029 (1975/68018). AF 95% confidence interval is 0.028. There are 28 homozygotes in gnomad4. There are 1227 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 28 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SCNN1A	NM_001038.6	c.*633G>T		3_prime_UTR_variant	13/13	ENST00000228916.7	NP_001029.1
SCNN1A	NM_001159575.2	c.*633G>T		3_prime_UTR_variant	13/13		NP_001153047.1
SCNN1A	NM_001159576.2	c.*633G>T		3_prime_UTR_variant	12/12		NP_001153048.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SCNN1A	ENST00000228916.7	c.*633G>T		3_prime_UTR_variant	13/13	1	NM_001038.6	ENSP00000228916	A2
SCNN1A	ENST00000360168.7	c.*633G>T		3_prime_UTR_variant	12/12	1		ENSP00000353292	A2
SCNN1A	ENST00000540037.5	c.*633G>T		3_prime_UTR_variant	11/11	1		ENSP00000440876

Frequencies

GnomAD3 genomes AF: 0.0179 AC: 2724 AN: 152166 Hom.: 28 Cov.: 32

Gnomad AFR AF: 0.00574

Gnomad AMI AF: 0.00220

Gnomad AMR AF: 0.0120

Gnomad ASJ AF: 0.00605

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0205

Gnomad FIN AF: 0.0151

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.0290

Gnomad OTH AF: 0.0196

GnomAD4 exome AF: 0.0220 AC: 52 AN: 2360 Hom.: 2 Cov.: 0 AF XY: 0.0191 AC XY: 25 AN XY: 1306

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00830

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0120

Gnomad4 FIN exome AF: 0.0714

Gnomad4 NFE exome AF: 0.0266

Gnomad4 OTH exome AF: 0.0556

GnomAD4 genome AF: 0.0179 AC: 2725 AN: 152284 Hom.: 28 Cov.: 32 AF XY: 0.0165 AC XY: 1227 AN XY: 74474

Gnomad4 AFR AF: 0.00573

Gnomad4 AMR AF: 0.0120

Gnomad4 ASJ AF: 0.00605

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.0207

Gnomad4 FIN AF: 0.0151

Gnomad4 NFE AF: 0.0290

Gnomad4 OTH AF: 0.0194

Alfa AF: 0.00582 Hom.: 0

Bravo AF: 0.0174

Asia WGS AF: 0.00520 AC: 19 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	May 16, 2021	See Variant Classification Assertion Criteria. -

Bronchiectasis with or without elevated sweat chloride 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. -

Pseudohypoaldosteronism, type IB1, autosomal recessive Benign:1

Likely 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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	0.66
DANN	Benign	0.57

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: rs62618735; hg19: chr12-6456406;