12-6375543-T-C

Variant names:

• chr12-6375543-T-C
• rs10849447
• NM_001038.6:c.-93A>G

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 9 publications found

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

Our verdict: Benign. The variant received -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 VariationId 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001038.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SCNN1A	NM_001038.6	MANE Select	c.-93A>G		5_prime_UTR	Exon 1 of 13	NP_001029.1	P37088-1
	LTBR	NM_001270987.2		c.-13T>C		5_prime_UTR	Exon 1 of 10	NP_001257916.1	P36941-2
	LTBR	NM_001414309.1		c.-13T>C		5_prime_UTR	Exon 1 of 10	NP_001401238.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SCNN1A	ENST00000228916.7	TSL:1 MANE Select	c.-93A>G		5_prime_UTR	Exon 1 of 13	ENSP00000228916.2	P37088-1
	SCNN1A	ENST00000868228.1		c.-44A>G		5_prime_UTR	Exon 1 of 13	ENSP00000538287.1
	SCNN1A	ENST00000868229.1		c.-84A>G		5_prime_UTR	Exon 1 of 13	ENSP00000538288.1

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

GnomAD2 exomes AF: 0.615 AC: 80071 AN: 130094 AF XY: 0.607

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 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

African (AFR) AF: 0.922 AC: 29092 AN: 31570

American (AMR) AF: 0.707 AC: 25222 AN: 35654

Ashkenazi Jewish (ASJ) AF: 0.316 AC: 7905 AN: 25050

East Asian (EAS) AF: 0.850 AC: 30313 AN: 35652

South Asian (SAS) AF: 0.653 AC: 51713 AN: 79202

European-Finnish (FIN) AF: 0.638 AC: 21261 AN: 33316

Middle Eastern (MID) AF: 0.398 AC: 2263 AN: 5684

European-Non Finnish (NFE) AF: 0.529 AC: 569802 AN: 1077862

Other (OTH) AF: 0.560 AC: 32376 AN: 57808

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

African (AFR) AF: 0.907 AC: 37592 AN: 41430

American (AMR) AF: 0.664 AC: 10122 AN: 15244

Ashkenazi Jewish (ASJ) AF: 0.312 AC: 1079 AN: 3458

East Asian (EAS) AF: 0.856 AC: 4400 AN: 5142

South Asian (SAS) AF: 0.679 AC: 3257 AN: 4800

European-Finnish (FIN) AF: 0.637 AC: 6710 AN: 10526

Middle Eastern (MID) AF: 0.381 AC: 112 AN: 294

European-Non Finnish (NFE) AF: 0.517 AC: 35016 AN: 67770

Other (OTH) AF: 0.571 AC: 1203 AN: 2106

Alfa AF: 0.536 Hom.: 4791

Bravo AF: 0.668

Asia WGS AF: 0.772 AC: 2684 AN: 3476

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Bronchiectasis with or without elevated sweat chloride 2 (1)
-	-	1	not provided (1)
-	-	1	Pseudohypoaldosteronism, type IB1, autosomal recessive (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	6.8
DANN	Benign	0.76
PhyloP100		0.48
PromoterAI		-0.021	Neutral
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs10849447; hg19: chr12-6484709;