16-23377383-C-T

Variant names:

• chr16-23377383-C-T
• rs74012901
• NM_000336.3:c.1401C>T

Variant summary

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

The NM_000336.3(SCNN1B):​c.1401C>T​(p.Ser467Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000496 in 1,614,074 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0027 (2 hom., cov: 32)
  • Exomes 𝑓: 0.00027 (0 hom.)
• Consequence: SCNN1B NM_000336.3 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -6.00
• Publications: 1 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, Labcorp Genetics (formerly Invitae)
• pseudohypoaldosteronism, type IB2, autosomal recessive

  Inheritance: AR Classification: DEFINITIVE Submitted by: Ambry Genetics
• bronchiectasis with or without elevated sweat chloride 1

  Inheritance: AD, SD Classification: STRONG, LIMITED Submitted by: PanelApp Australia, Ambry Genetics
• pseudohypoaldosteronism, type IB1, autosomal recessive

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

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.6).
• BP6: Variant 16-23377383-C-T is Benign according to our data. Variant chr16-23377383-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 165169.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-6 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00269 (410/152300) while in subpopulation AFR AF = 0.00935 (389/41584). AF 95% confidence interval is 0.00859. There are 2 homozygotes in GnomAd4. There are 198 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 2 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.1401C>T	p.Ser467Ser	synonymous	Exon 10 of 13	NP_000327.2
	SCNN1B	NM_001410900.1		c.1293C>T	p.Ser431Ser	synonymous	Exon 9 of 12	NP_001397829.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SCNN1B	ENST00000343070.7	TSL:1 MANE Select	c.1401C>T	p.Ser467Ser	synonymous	Exon 10 of 13	ENSP00000345751.2
	SCNN1B	ENST00000307331.9	TSL:5	c.1536C>T	p.Ser512Ser	synonymous	Exon 11 of 14	ENSP00000302874.5
	SCNN1B	ENST00000962247.1		c.1497C>T	p.Ser499Ser	synonymous	Exon 10 of 13	ENSP00000632306.1

Frequencies

GnomAD3 genomes AF: 0.00269 AC: 409 AN: 152182 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.00936

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00111

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: 0.0000294

Gnomad OTH AF: 0.000957

GnomAD2 exomes AF: 0.000760 AC: 191 AN: 251468 AF XY: 0.000486

Gnomad AFR exome AF: 0.0106

Gnomad AMR exome AF: 0.000318

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000352

Gnomad OTH exome AF: 0.000489

GnomAD4 exome AF: 0.000267 AC: 390 AN: 1461774 Hom.: 0 Cov.: 33 AF XY: 0.000206 AC XY: 150 AN XY: 727212

African (AFR) AF: 0.00947 AC: 317 AN: 33476

American (AMR) AF: 0.000492 AC: 22 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39700

South Asian (SAS) AF: 0.0000464 AC: 4 AN: 86252

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53402

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

European-Non Finnish (NFE) AF: 0.0000108 AC: 12 AN: 1111928

Other (OTH) AF: 0.000530 AC: 32 AN: 60390

GnomAD4 genome AF: 0.00269 AC: 410 AN: 152300 Hom.: 2 Cov.: 32 AF XY: 0.00266 AC XY: 198 AN XY: 74480

African (AFR) AF: 0.00935 AC: 389 AN: 41584

American (AMR) AF: 0.00111 AC: 17 AN: 15294

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5174

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

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10616

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

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 68014

Other (OTH) AF: 0.000947 AC: 2 AN: 2112

Alfa AF: 0.00113 Hom.: 1

Bravo AF: 0.00339

Asia WGS AF: 0.00144 AC: 5 AN: 3478

ClinVar

ClinVar submissions as Germline

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 1 (1)
-	-	1	Liddle syndrome 1 (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	-0.60
CADD	Benign	0.43
DANN	Benign	0.59
PhyloP100		-6.0
Mutation Taster		=100/0	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: rs74012901; hg19: chr16-23388704;