rs72646501

Variant names:

• chr16-23192509-C-A
• rs72646501
• NM_001039.4:c.776C>A

Your query was ambiguous. Multiple possible variants found:

• chr16-23192509-C-A
• chr16-23192509-C-T

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 0P and 1B. BP4

The NM_001039.4(SCNN1G):​c.776C>A​(p.Thr259Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000651 in 1,612,498 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00039 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00068 (1 hom.)
• Consequence: SCNN1G NM_001039.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4 B:1
• Conservation: PhyloP100: 2.15
• Publications: 5 publications found

Genes affected

SCNN1G (HGNC:10602): (sodium channel epithelial 1 subunit gamma) 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 gamma subunit, and mutations in this gene have been associated with Liddle syndrome. [provided by RefSeq, Apr 2009]

SCNN1G Gene-Disease associations (from GenCC):

• Liddle syndrome

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
• Liddle syndrome 2

  Inheritance: AD Classification: STRONG, MODERATE Submitted by: Laboratory for Molecular Medicine, Ambry Genetics, PanelApp Australia, Labcorp Genetics (formerly Invitae)
• pseudohypoaldosteronism, type IB1, autosomal recessive

  Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: PanelApp Australia, Labcorp Genetics (formerly Invitae), Orphanet

ACMG classification

Our verdict: Likely_benign. The variant received -1 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.3401159).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001039.4. 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
	SCNN1G	NM_001039.4	MANE Select	c.776C>A	p.Thr259Asn	missense	Exon 4 of 13	NP_001030.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SCNN1G	ENST00000300061.3	TSL:1 MANE Select	c.776C>A	p.Thr259Asn	missense	Exon 4 of 13	ENSP00000300061.2	P51170
	SCNN1G	ENST00000876142.1		c.776C>A	p.Thr259Asn	missense	Exon 3 of 12	ENSP00000546201.1
	SCNN1G	ENST00000876141.1		c.776C>A	p.Thr259Asn	missense	Exon 4 of 13	ENSP00000546200.1

Frequencies

GnomAD3 genomes AF: 0.000394 AC: 60 AN: 152110 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.0000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000942

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000765

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.000366 AC: 92 AN: 251270 AF XY: 0.000376

Gnomad AFR exome AF: 0.0000616

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000462

Gnomad NFE exome AF: 0.000687

Gnomad OTH exome AF: 0.000326

GnomAD4 exome AF: 0.000677 AC: 989 AN: 1460388 Hom.: 1 Cov.: 32 AF XY: 0.000624 AC XY: 453 AN XY: 726532

African (AFR) AF: 0.000120 AC: 4 AN: 33430

American (AMR) AF: 0.0000447 AC: 2 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.00 AC: 0 AN: 86180

European-Finnish (FIN) AF: 0.000356 AC: 19 AN: 53412

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4574

European-Non Finnish (NFE) AF: 0.000817 AC: 908 AN: 1111966

Other (OTH) AF: 0.000929 AC: 56 AN: 60274

GnomAD4 genome AF: 0.000394 AC: 60 AN: 152110 Hom.: 0 Cov.: 31 AF XY: 0.000363 AC XY: 27 AN XY: 74308

African (AFR) AF: 0.0000724 AC: 3 AN: 41422

American (AMR) AF: 0.000196 AC: 3 AN: 15272

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5172

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.0000942 AC: 1 AN: 10614

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.000765 AC: 52 AN: 68016

Other (OTH) AF: 0.000478 AC: 1 AN: 2092

Alfa AF: 0.000727 Hom.: 0

Bravo AF: 0.000340

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.000778 AC: 3

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000930 AC: 8

ExAC AF: 0.000296 AC: 36

EpiCase AF: 0.000872

EpiControl AF: 0.000771

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	2	-	not provided (2)
-	-	1	Liddle syndrome 2 (1)
-	1	-	not specified (1)
-	1	-	Pseudohypoaldosteronism, type IB1, autosomal recessive (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.35	T
BayesDel_noAF	Benign	-0.32
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Benign	0.36	T
Eigen	Uncertain	0.47
Eigen_PC	Uncertain	0.41
FATHMM_MKL	Uncertain	0.83	D
LIST_S2	Benign	0.76	T
M_CAP	Benign	0.036	D
MetaRNN	Benign	0.34	T
MetaSVM	Uncertain	0.077	D
MutationAssessor	Uncertain	2.6	M
PhyloP100		2.1
PrimateAI	Uncertain	0.58	T
PROVEAN	Uncertain	-2.7	D
REVEL	Uncertain	0.35
Sift	Benign	0.053	T
Sift4G	Uncertain	0.047	D
Polyphen		0.99	D
Vest4		0.19
MVP		0.74
MPC		0.35
ClinPred		0.12	T
GERP RS		4.2
Varity_R		0.62
gMVP		0.79
Mutation Taster		=82/18	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs72646501; hg19: chr16-23203830;