rs17376426

Positions:

• chr1-11848110-C-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The ENST00000376476.1(NPPA):​c.-57G>A variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0277 in 305,938 control chromosomes in the GnomAD database, including 188 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.026 (87 hom., cov: 32)
  • Exomes 𝑓: 0.029 (101 hom.)
• Consequence: NPPA ENST00000376476.1 5_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.21

Genes affected

NPPA (HGNC:7939): (natriuretic peptide A) The protein encoded by this gene belongs to the natriuretic peptide family. Natriuretic peptides are implicated in the control of extracellular fluid volume and electrolyte homeostasis. This protein is synthesized as a large precursor (containing a signal peptide), which is processed to release a peptide from the N-terminus with similarity to vasoactive peptide, cardiodilatin, and another peptide from the C-terminus with natriuretic-diuretic activity. Mutations in this gene have been associated with atrial fibrillation familial type 6. This gene is located adjacent to another member of the natriuretic family of peptides on chromosome 1. [provided by RefSeq, Oct 2015]

CLCN6 (HGNC:2024): (chloride voltage-gated channel 6) This gene encodes a member of the voltage-dependent chloride channel protein family. Members of this family can function as either chloride channels or antiporters. This protein is primarily localized to late endosomes and functions as a chloride/proton antiporter. Alternate splicing results in both coding and non-coding variants. Additional alternately spliced variants have been described but their full-length structure is unknown. [provided by RefSeq, Mar 2012]

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP6: Variant 1-11848110-C-T is Benign according to our data. Variant chr1-11848110-C-T is described in ClinVar as [Benign]. Clinvar id is 1252882.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0261 (3979/152346) while in subpopulation NFE AF= 0.0389 (2648/68034). AF 95% confidence interval is 0.0377. There are 87 homozygotes in gnomad4. There are 1946 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 87 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NPPA	ENST00000376476.1	c.-57G>A		5_prime_UTR_variant	1/3	3		ENSP00000365659
CLCN6	ENST00000400892.3			downstream_gene_variant		3		ENSP00000496938

Frequencies

GnomAD3 genomes AF: 0.0261 AC: 3978 AN: 152230 Hom.: 87 Cov.: 32

Gnomad AFR AF: 0.00598

Gnomad AMI AF: 0.0373

Gnomad AMR AF: 0.0179

Gnomad ASJ AF: 0.00720

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00621

Gnomad FIN AF: 0.0627

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0389

Gnomad OTH AF: 0.0248

GnomAD4 exome AF: 0.0293 AC: 4496 AN: 153592 Hom.: 101 Cov.: 0 AF XY: 0.0265 AC XY: 2200 AN XY: 83010

Gnomad4 AFR exome AF: 0.00384

Gnomad4 AMR exome AF: 0.0164

Gnomad4 ASJ exome AF: 0.00978

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00830

Gnomad4 FIN exome AF: 0.0681

Gnomad4 NFE exome AF: 0.0386

Gnomad4 OTH exome AF: 0.0324

GnomAD4 genome AF: 0.0261 AC: 3979 AN: 152346 Hom.: 87 Cov.: 32 AF XY: 0.0261 AC XY: 1946 AN XY: 74496

Gnomad4 AFR AF: 0.00596

Gnomad4 AMR AF: 0.0179

Gnomad4 ASJ AF: 0.00720

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00622

Gnomad4 FIN AF: 0.0627

Gnomad4 NFE AF: 0.0389

Gnomad4 OTH AF: 0.0246

Alfa AF: 0.0334 Hom.: 37

Bravo AF: 0.0208

Asia WGS AF: 0.00404 AC: 14 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jun 21, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	14
DANN	Benign	0.62

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs17376426; hg19: chr1-11908167;