rs61759915

Variant names:

• chr16-23367851-T-C
• rs61759915
• NM_000336.3:c.777-5T>C

Variant summary

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

The NM_000336.3(SCNN1B):​c.777-5T>C variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00432 in 1,611,058 control chromosomes in the GnomAD database, including 40 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0034 (4 hom., cov: 34)
  • Exomes 𝑓: 0.0044 (36 hom.)
• Consequence: SCNN1B NM_000336.3 splice_region, intron
• Scores: Splicing: ADA: 0.004590
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: 1.59
• Publications: 0 publications found

Genes affected

SCNN1B (HGNC:10600): (sodium channel epithelial 1 subunit beta) 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 beta subunit, and mutations in this gene have been associated with pseudohypoaldosteronism type 1 (PHA1), and Liddle syndrome. [provided by RefSeq, Apr 2009]

SCNN1B Gene-Disease associations (from GenCC):

• Liddle syndrome 1

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, PanelApp Australia, Labcorp Genetics (formerly Invitae)
• pseudohypoaldosteronism, type IB2, autosomal recessive

  Inheritance: AR Classification: DEFINITIVE Submitted by: Ambry Genetics
• pseudohypoaldosteronism, type IB1, autosomal recessive

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

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• bronchiectasis with or without elevated sweat chloride 1

  Inheritance: SD Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.74).
• BP6: Variant 16-23367851-T-C is Benign according to our data. Variant chr16-23367851-T-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 227060.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.0034 (518/152360) while in subpopulation SAS AF = 0.0129 (62/4824). AF 95% confidence interval is 0.0103. There are 4 homozygotes in GnomAd4. There are 245 alleles in the male GnomAd4 subpopulation. Median coverage is 34. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 4 AR,AD,SD gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000336.3. 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
	SCNN1B	NM_000336.3	MANE Select	c.777-5T>C		splice_region intron	N/A	NP_000327.2	B2R812
	SCNN1B	NM_001410900.1		c.777-5T>C		splice_region intron	N/A	NP_001397829.1	H3BQ95

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SCNN1B	ENST00000343070.7	TSL:1 MANE Select	c.777-5T>C		splice_region intron	N/A	ENSP00000345751.2	P51168-1
	SCNN1B	ENST00000962247.1		c.868T>C	p.Phe290Leu	missense	Exon 5 of 13	ENSP00000632306.1
	SCNN1B	ENST00000307331.9	TSL:5	c.912-5T>C		splice_region intron	N/A	ENSP00000302874.5	P51168-2

Frequencies

GnomAD3 genomes AF: 0.00339 AC: 516 AN: 152242 Hom.: 4 Cov.: 34

Gnomad AFR AF: 0.000844

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00137

Gnomad ASJ AF: 0.00634

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.0124

Gnomad FIN AF: 0.00198

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00517

Gnomad OTH AF: 0.00191

GnomAD2 exomes AF: 0.00409 AC: 1029 AN: 251480 AF XY: 0.00455

Gnomad AFR exome AF: 0.000738

Gnomad AMR exome AF: 0.000867

Gnomad ASJ exome AF: 0.00794

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.00139

Gnomad NFE exome AF: 0.00458

Gnomad OTH exome AF: 0.00342

GnomAD4 exome AF: 0.00442 AC: 6442 AN: 1458698 Hom.: 36 Cov.: 31 AF XY: 0.00465 AC XY: 3379 AN XY: 725936

African (AFR) AF: 0.000629 AC: 21 AN: 33386

American (AMR) AF: 0.000805 AC: 36 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00739 AC: 193 AN: 26120

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39688

South Asian (SAS) AF: 0.0104 AC: 899 AN: 86194

European-Finnish (FIN) AF: 0.00127 AC: 68 AN: 53416

Middle Eastern (MID) AF: 0.00416 AC: 24 AN: 5768

European-Non Finnish (NFE) AF: 0.00448 AC: 4974 AN: 1109120

Other (OTH) AF: 0.00375 AC: 226 AN: 60284

GnomAD4 genome AF: 0.00340 AC: 518 AN: 152360 Hom.: 4 Cov.: 34 AF XY: 0.00329 AC XY: 245 AN XY: 74502

African (AFR) AF: 0.000841 AC: 35 AN: 41596

American (AMR) AF: 0.00137 AC: 21 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.00634 AC: 22 AN: 3470

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5182

South Asian (SAS) AF: 0.0129 AC: 62 AN: 4824

European-Finnish (FIN) AF: 0.00198 AC: 21 AN: 10624

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

European-Non Finnish (NFE) AF: 0.00517 AC: 352 AN: 68038

Other (OTH) AF: 0.00189 AC: 4 AN: 2116

Alfa AF: 0.00418 Hom.: 0

Bravo AF: 0.00300

Asia WGS AF: 0.00462 AC: 16 AN: 3478

EpiCase AF: 0.00431

EpiControl AF: 0.00439

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	-	2	not specified (2)
-	-	1	Bronchiectasis with or without elevated sweat chloride 1 (1)
-	-	1	Liddle syndrome 1 (1)
-	-	1	Pseudohypoaldosteronism, type IB1, autosomal recessive (1)
-	-	1	SCNN1B-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.74
CADD	Benign	11
DANN	Benign	0.79
PhyloP100		1.6
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0046
dbscSNV1_RF	Benign	0.20
SpliceAI score (max)		0.080		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: rs61759915; hg19: chr16-23379172;