ENST00000360168.7:c.150T>C

Variant names:

• chr12-6374811-A-G
• rs61759919
• ENST00000360168.7:c.150T>C

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The ENST00000360168.7(SCNN1A):​c.150T>C​(p.Pro50Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00112 in 1,613,806 control chromosomes in the GnomAD database, including 15 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0062 (6 hom., cov: 32)
  • Exomes 𝑓: 0.00059 (9 hom.)
• Consequence: SCNN1A ENST00000360168.7 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -1.09
• 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: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).
• BP6: Variant 12-6374811-A-G is Benign according to our data. Variant chr12-6374811-A-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 227058.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.09 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00618 (940/152050) while in subpopulation AFR AF = 0.0217 (900/41466). AF 95% confidence interval is 0.0205. There are 6 homozygotes in GnomAd4. There are 472 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 6 AR,Unknown,AD gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000360168.7. 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.-28T>C		5_prime_UTR	Exon 2 of 13	NP_001029.1	P37088-1
	SCNN1A	NM_001159576.2		c.150T>C	p.Pro50Pro	synonymous	Exon 1 of 12	NP_001153048.1	P37088-2
	SCNN1A	NM_001159575.2		c.42T>C	p.Pro14Pro	synonymous	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.150T>C	p.Pro50Pro	synonymous	Exon 1 of 12	ENSP00000353292.3	P37088-2
	SCNN1A	ENST00000228916.7	TSL:1 MANE Select	c.-28T>C		5_prime_UTR	Exon 2 of 13	ENSP00000228916.2	P37088-1
	SCNN1A	ENST00000543768.1	TSL:2	c.42T>C	p.Pro14Pro	synonymous	Exon 2 of 13	ENSP00000438739.1	P37088-6

Frequencies

GnomAD3 genomes AF: 0.00619 AC: 940 AN: 151932 Hom.: 6 Cov.: 32

Gnomad AFR AF: 0.0218

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00164

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: 0.0000588

Gnomad OTH AF: 0.00527

GnomAD2 exomes AF: 0.00166 AC: 416 AN: 251302 AF XY: 0.00112

Gnomad AFR exome AF: 0.0238

Gnomad AMR exome AF: 0.000636

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000528

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.000594 AC: 868 AN: 1461756 Hom.: 9 Cov.: 32 AF XY: 0.000494 AC XY: 359 AN XY: 727170

African (AFR) AF: 0.0218 AC: 728 AN: 33456

American (AMR) AF: 0.000760 AC: 34 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26128

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

South Asian (SAS) AF: 0.0000696 AC: 6 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53368

Middle Eastern (MID) AF: 0.000347 AC: 2 AN: 5766

European-Non Finnish (NFE) AF: 0.0000234 AC: 26 AN: 1111980

Other (OTH) AF: 0.00119 AC: 72 AN: 60384

GnomAD4 genome AF: 0.00618 AC: 940 AN: 152050 Hom.: 6 Cov.: 32 AF XY: 0.00635 AC XY: 472 AN XY: 74346

African (AFR) AF: 0.0217 AC: 900 AN: 41466

American (AMR) AF: 0.00164 AC: 25 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5156

South Asian (SAS) AF: 0.00 AC: 0 AN: 4790

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10608

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

European-Non Finnish (NFE) AF: 0.0000588 AC: 4 AN: 67972

Other (OTH) AF: 0.00522 AC: 11 AN: 2108

Alfa AF: 0.00311 Hom.: 4

Bravo AF: 0.00656

Asia WGS AF: 0.000577 AC: 3 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.000178

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)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	1.3
DANN	Benign	0.66
PhyloP100		-1.1
PromoterAI		0.0052	Neutral
Mutation Taster		=299/1	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: rs61759919; hg19: chr12-6483977;