chr12-6374831-T-C

Variant names:

• chr12-6374831-T-C
• rs150809388
• ENST00000360168.7:c.130A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001159576.2(SCNN1A):​c.130A>G​(p.Lys44Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00125 in 1,614,058 control chromosomes in the GnomAD database, including 18 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0066 (4 hom., cov: 32)
  • Exomes 𝑓: 0.00069 (14 hom.)
• Consequence: SCNN1A NM_001159576.2 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -0.949
• Publications: 3 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 (MetaRNN=0.0031102896).
• BP6: Variant 12-6374831-T-C is Benign according to our data. Variant chr12-6374831-T-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 310155.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00658 (1001/152210) while in subpopulation AFR AF = 0.0223 (924/41518). AF 95% confidence interval is 0.0211. There are 4 homozygotes in GnomAd4. There are 447 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 4 AR,Unknown,AD gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001159576.2. 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.-48A>G		5_prime_UTR	Exon 2 of 13	NP_001029.1	P37088-1
	SCNN1A	NM_001159576.2		c.130A>G	p.Lys44Glu	missense	Exon 1 of 12	NP_001153048.1	P37088-2
	SCNN1A	NM_001159575.2		c.22A>G	p.Lys8Glu	missense	Exon 2 of 13	NP_001153047.1	P37088-6

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SCNN1A	ENST00000360168.7	TSL:1	c.130A>G	p.Lys44Glu	missense	Exon 1 of 12	ENSP00000353292.3	P37088-2
	SCNN1A	ENST00000228916.7	TSL:1 MANE Select	c.-48A>G		5_prime_UTR	Exon 2 of 13	ENSP00000228916.2	P37088-1
	SCNN1A	ENST00000543768.1	TSL:2	c.22A>G	p.Lys8Glu	missense	Exon 2 of 13	ENSP00000438739.1	P37088-6

Frequencies

GnomAD3 genomes AF: 0.00659 AC: 1003 AN: 152092 Hom.: 4 Cov.: 32

Gnomad AFR AF: 0.0224

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00406

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00623

GnomAD2 exomes AF: 0.00177 AC: 445 AN: 251194 AF XY: 0.00138

Gnomad AFR exome AF: 0.0244

Gnomad AMR exome AF: 0.00121

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000880

Gnomad OTH exome AF: 0.000653

GnomAD4 exome AF: 0.000691 AC: 1010 AN: 1461848 Hom.: 14 Cov.: 32 AF XY: 0.000579 AC XY: 421 AN XY: 727224

African (AFR) AF: 0.0240 AC: 805 AN: 33480

American (AMR) AF: 0.00163 AC: 73 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.000116 AC: 10 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53378

Middle Eastern (MID) AF: 0.00104 AC: 6 AN: 5768

European-Non Finnish (NFE) AF: 0.0000198 AC: 22 AN: 1112008

Other (OTH) AF: 0.00156 AC: 94 AN: 60396

GnomAD4 genome AF: 0.00658 AC: 1001 AN: 152210 Hom.: 4 Cov.: 32 AF XY: 0.00601 AC XY: 447 AN XY: 74436

African (AFR) AF: 0.0223 AC: 924 AN: 41518

American (AMR) AF: 0.00405 AC: 62 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5168

South Asian (SAS) AF: 0.00 AC: 0 AN: 4818

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 67996

Other (OTH) AF: 0.00617 AC: 13 AN: 2108

Alfa AF: 0.00241 Hom.: 3

Bravo AF: 0.00762

ESP6500AA AF: 0.0254 AC: 112

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00231 AC: 280

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.000109

EpiControl AF: 0.00

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Bronchiectasis with or without elevated sweat chloride 2 (1)
-	-	1	not specified (1)
-	-	1	Pseudohypoaldosteronism, type IB1, autosomal recessive (1)
-	-	1	SCNN1A-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.084
BayesDel_addAF	Benign	-0.43	T
BayesDel_noAF	Benign	-0.37
CADD	Benign	6.7
DANN	Benign	0.97
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.031	N
LIST_S2	Benign	0.36	T
MetaRNN	Benign	0.0031	T
MetaSVM	Benign	-0.83	T
PhyloP100		-0.95
PrimateAI	Benign	0.29	T
PROVEAN	Benign	-0.31	N
REVEL	Benign	0.16
Sift	Uncertain	0.026	D
Sift4G	Benign	0.084	T
Polyphen		0.0	B
Vest4		0.15
MVP		0.32
MPC		0.19
ClinPred		0.0060	T
GERP RS		-3.0
PromoterAI		-0.017	Neutral
gMVP		0.32
Mutation Taster		=96/4	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

Other links and lift over

dbSNP: rs150809388; hg19: chr12-6483997;