rs2228576

Variant names:

• chr12-6347896-T-A
• rs2228576
• NM_001038.6:c.1987A>T

Your query was ambiguous. Multiple possible variants found:

• chr12-6347896-T-A
• chr12-6347896-T-C
• chr12-6347896-T-G

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001038.6(SCNN1A):​c.1987A>T​(p.Thr663Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000138 in 1,446,050 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T663A) has been classified as Benign.

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: SCNN1A NM_001038.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.388
• Publications: 93 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]

SCNN1A Gene-Disease associations (from GenCC):

• pseudohypoaldosteronism, type IB1, autosomal recessive

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: ClinGen, Laboratory for Molecular Medicine, Orphanet, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• bronchiectasis with or without elevated sweat chloride 2

  Inheritance: Unknown, AD Classification: STRONG, MODERATE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), PanelApp Australia, Ambry Genetics
• Brugada syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Liddle syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Liddle syndrome 3

  Inheritance: Unknown, AD Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.06232226).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SCNN1A	NM_001038.6	c.1987A>T	p.Thr663Ser	missense_variant	Exon 13 of 13	ENST00000228916.7	NP_001029.1
SCNN1A	NM_001159576.2	c.2164A>T	p.Thr722Ser	missense_variant	Exon 12 of 12		NP_001153048.1
SCNN1A	NM_001159575.2	c.2056A>T	p.Thr686Ser	missense_variant	Exon 13 of 13		NP_001153047.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SCNN1A	ENST00000228916.7	c.1987A>T	p.Thr663Ser	missense_variant	Exon 13 of 13	1	NM_001038.6	ENSP00000228916.2

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD2 exomes AF: 0.00000451 AC: 1 AN: 221868 AF XY: 0.00000824

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000103

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000138 AC: 2 AN: 1446050 Hom.: 0 Cov.: 41 AF XY: 0.00000279 AC XY: 2 AN XY: 718096

African (AFR) AF: 0.00 AC: 0 AN: 33236

American (AMR) AF: 0.00 AC: 0 AN: 42976

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25812

East Asian (EAS) AF: 0.00 AC: 0 AN: 39414

South Asian (SAS) AF: 0.00 AC: 0 AN: 84236

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51468

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4744

European-Non Finnish (NFE) AF: 0.00000181 AC: 2 AN: 1104464

Other (OTH) AF: 0.00 AC: 0 AN: 59700

GnomAD4 genome Cov.: 34

Alfa AF: 0.00 Hom.: 54010

ExAC AF: 0.00000839 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.063
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Benign	-0.52
CADD	Benign	1.6
DANN	Benign	0.74
DEOGEN2	Benign	0.088	.;.;T;.
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.016	N
LIST_S2	Benign	0.26	T;T;T;T
M_CAP	Benign	0.029	D
MetaRNN	Benign	0.062	T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.69	.;.;N;.
PhyloP100		-0.39
PrimateAI	Benign	0.42	T
PROVEAN	Benign	0.20	N;N;N;N
REVEL	Benign	0.061
Sift	Benign	0.035	D;T;T;D
Sift4G	Benign	0.35	T;T;T;T
Polyphen		0.0020	B;.;B;.
Vest4		0.085
MutPred		0.12		.;.;Gain of phosphorylation at T663 (P = 0.094);.;
MVP		0.49
MPC		0.11
ClinPred		0.052	T
GERP RS		1.9
Varity_R		0.039
gMVP		0.13
Mutation Taster		=97/3	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: rs2228576; hg19: chr12-6457062;