12-6375503-A-G

Variant names:

• chr12-6375503-A-G
• rs772498945
• NM_001038.6:c.-55+2T>C

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 8P and 5B. PVS1 BP6 BS1

The NM_001038.6(SCNN1A):​c.-55+2T>C variant causes a splice donor, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00174 in 1,531,786 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0011 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0018 (1 hom.)
• Consequence: SCNN1A NM_001038.6 splice_donor, intron
• Scores: Splicing: ADA: 0.03024
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:1
• Conservation: PhyloP100: 1.79
• Publications: 1 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: Uncertain_significance. The variant received 3 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, LoF is a know mechanism of disease,
• BP6: Variant 12-6375503-A-G is Benign according to our data. Variant chr12-6375503-A-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 591722.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00113 (171/150702) while in subpopulation NFE AF = 0.00217 (147/67626). AF 95% confidence interval is 0.00189. There are 0 homozygotes in GnomAd4. There are 71 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SCNN1A	NM_001038.6	MANE Select	c.-55+2T>C		splice_donor intron	N/A	NP_001029.1
	LTBR	NM_001270987.2		c.-53A>G		5_prime_UTR	Exon 1 of 10	NP_001257916.1
	LTBR	NM_001414309.1		c.-53A>G		5_prime_UTR	Exon 1 of 10	NP_001401238.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SCNN1A	ENST00000228916.7	TSL:1 MANE Select	c.-55+2T>C		splice_donor intron	N/A	ENSP00000228916.2
	SCNN1A	ENST00000542260.1	TSL:4	n.61T>C		non_coding_transcript_exon	Exon 1 of 2
	LTBR	ENST00000546296.5	TSL:4	n.459A>G		non_coding_transcript_exon	Exon 1 of 3

Frequencies

GnomAD3 genomes AF: 0.00113 AC: 171 AN: 150702 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000391

Gnomad AMI AF: 0.00221

Gnomad AMR AF: 0.000264

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000193

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00217

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00181 AC: 2499 AN: 1381084 Hom.: 1 Cov.: 32 AF XY: 0.00172 AC XY: 1173 AN XY: 681476

African (AFR) AF: 0.000349 AC: 11 AN: 31502

American (AMR) AF: 0.000533 AC: 19 AN: 35656

Ashkenazi Jewish (ASJ) AF: 0.0000400 AC: 1 AN: 25020

East Asian (EAS) AF: 0.00 AC: 0 AN: 35644

South Asian (SAS) AF: 0.00 AC: 0 AN: 79204

European-Finnish (FIN) AF: 0.000450 AC: 15 AN: 33300

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5572

European-Non Finnish (NFE) AF: 0.00216 AC: 2332 AN: 1077438

Other (OTH) AF: 0.00210 AC: 121 AN: 57748

GnomAD4 genome AF: 0.00113 AC: 171 AN: 150702 Hom.: 0 Cov.: 32 AF XY: 0.000966 AC XY: 71 AN XY: 73526

African (AFR) AF: 0.000391 AC: 16 AN: 40890

American (AMR) AF: 0.000264 AC: 4 AN: 15170

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5092

South Asian (SAS) AF: 0.00 AC: 0 AN: 4778

European-Finnish (FIN) AF: 0.000193 AC: 2 AN: 10382

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.00217 AC: 147 AN: 67626

Other (OTH) AF: 0.00 AC: 0 AN: 2078

Alfa AF: 0.00171 Hom.: 0

Bravo AF: 0.00109

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	2	-	not provided (2)
-	-	1	Bronchiectasis with or without elevated sweat chloride 2 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.36
CADD	Benign	23
DANN	Benign	0.95
PhyloP100		1.8
PromoterAI		0.086	Neutral
Mutation Taster		=30/70	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.030
dbscSNV1_RF	Benign	0.15
SpliceAI score (max)		0.69		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.69		Position offset: 2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs772498945; hg19: chr12-6484669;