chr12-6347896-T-C

Variant names:

• chr12-6347896-T-C
• rs2228576
• NM_001038.6:c.1987A>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.1987A>G​(p.Thr663Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.681 in 1,596,108 control chromosomes in the GnomAD database, including 374,537 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T663V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.75 (43519 hom., cov: 34)
  • Exomes 𝑓: 0.67 (331018 hom.)
• Consequence: SCNN1A NM_001038.6 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:13
• 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: Labcorp Genetics (formerly Invitae), Ambry Genetics, Orphanet, PanelApp Australia, ClinGen, Laboratory for Molecular Medicine
• bronchiectasis with or without elevated sweat chloride 2

  Inheritance: Unknown, AD Classification: 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=9.429439E-7).
• BP6: Variant 12-6347896-T-C is Benign according to our data. Variant chr12-6347896-T-C is described in ClinVar as Benign. ClinVar VariationId is 165164.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.897 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.1987A>G	p.Thr663Ala	missense	Exon 13 of 13	NP_001029.1	P37088-1
	SCNN1A	NM_001159576.2		c.2164A>G	p.Thr722Ala	missense	Exon 12 of 12	NP_001153048.1	P37088-2
	SCNN1A	NM_001159575.2		c.2056A>G	p.Thr686Ala	missense	Exon 13 of 13	NP_001153047.1	P37088-6

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SCNN1A	ENST00000228916.7	TSL:1 MANE Select	c.1987A>G	p.Thr663Ala	missense	Exon 13 of 13	ENSP00000228916.2	P37088-1
	SCNN1A	ENST00000360168.7	TSL:1	c.2164A>G	p.Thr722Ala	missense	Exon 12 of 12	ENSP00000353292.3	P37088-2
	SCNN1A	ENST00000540037.5	TSL:1	c.1087A>G	p.Thr363Ala	missense	Exon 11 of 11	ENSP00000440876.1	F5GXE6

Frequencies

GnomAD3 genomes AF: 0.747 AC: 113634 AN: 152042 Hom.: 43465 Cov.: 34

Gnomad AFR AF: 0.905

Gnomad AMI AF: 0.654

Gnomad AMR AF: 0.775

Gnomad ASJ AF: 0.761

Gnomad EAS AF: 0.508

Gnomad SAS AF: 0.745

Gnomad FIN AF: 0.706

Gnomad MID AF: 0.761

Gnomad NFE AF: 0.671

Gnomad OTH AF: 0.742

GnomAD2 exomes AF: 0.694 AC: 154065 AN: 221868 AF XY: 0.691

Gnomad AFR exome AF: 0.909

Gnomad AMR exome AF: 0.760

Gnomad ASJ exome AF: 0.753

Gnomad EAS exome AF: 0.499

Gnomad FIN exome AF: 0.696

Gnomad NFE exome AF: 0.660

Gnomad OTH exome AF: 0.701

GnomAD4 exome AF: 0.674 AC: 973645 AN: 1443946 Hom.: 331018 Cov.: 41 AF XY: 0.676 AC XY: 484796 AN XY: 717104

African (AFR) AF: 0.917 AC: 30439 AN: 33212

American (AMR) AF: 0.761 AC: 32694 AN: 42948

Ashkenazi Jewish (ASJ) AF: 0.752 AC: 19415 AN: 25802

East Asian (EAS) AF: 0.560 AC: 22053 AN: 39384

South Asian (SAS) AF: 0.741 AC: 62408 AN: 84186

European-Finnish (FIN) AF: 0.706 AC: 36332 AN: 51450

Middle Eastern (MID) AF: 0.749 AC: 3544 AN: 4734

European-Non Finnish (NFE) AF: 0.658 AC: 725887 AN: 1102578

Other (OTH) AF: 0.685 AC: 40873 AN: 59652

GnomAD4 genome AF: 0.748 AC: 113745 AN: 152162 Hom.: 43519 Cov.: 34 AF XY: 0.749 AC XY: 55726 AN XY: 74386

African (AFR) AF: 0.905 AC: 37600 AN: 41552

American (AMR) AF: 0.774 AC: 11842 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.761 AC: 2640 AN: 3470

East Asian (EAS) AF: 0.508 AC: 2621 AN: 5158

South Asian (SAS) AF: 0.745 AC: 3596 AN: 4826

European-Finnish (FIN) AF: 0.706 AC: 7470 AN: 10576

Middle Eastern (MID) AF: 0.750 AC: 219 AN: 292

European-Non Finnish (NFE) AF: 0.671 AC: 45597 AN: 67974

Other (OTH) AF: 0.742 AC: 1564 AN: 2108

Alfa AF: 0.689 Hom.: 54010

Bravo AF: 0.753

TwinsUK AF: 0.659 AC: 2443

ALSPAC AF: 0.648 AC: 2498

ESP6500AA AF: 0.900 AC: 3760

ESP6500EA AF: 0.693 AC: 5675

ExAC AF: 0.680 AC: 81091

Asia WGS AF: 0.658 AC: 2292 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not specified (5)
-	-	3	not provided (3)
-	-	2	Bronchiectasis with or without elevated sweat chloride 2 (2)
-	-	2	Pseudohypoaldosteronism, type IB1, autosomal recessive (2)
-	-	1	Liddle syndrome 3 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.050
BayesDel_addAF	Benign	-0.73	T
BayesDel_noAF	Benign	-0.68
CADD	Benign	0.25
DANN	Benign	0.46
DEOGEN2	Benign	0.073	T
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.00050	N
LIST_S2	Benign	0.22	T
MetaRNN	Benign	9.4e-7	T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	-1.6	N
PhyloP100		-0.39
PrimateAI	Benign	0.44	T
PROVEAN	Benign	0.28	N
REVEL	Benign	0.14
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.011
MPC		0.12
ClinPred		0.0029	T
GERP RS		1.9
Varity_R		0.031
gMVP		0.15
Mutation Taster		=100/0	polymorphism (auto)

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; COSMIC: COSV57434232; COSMIC: COSV57434232;