ENST00000376476.1:c.-57G>A

Variant names:

• chr1-11848110-C-T
• rs17376426
• ENST00000376476.1:c.-57G>A

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 9 publications found

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]

CLCN6 Gene-Disease associations (from GenCC):

• neurodegeneration, childhood-onset, with hypotonia, respiratory insufficiency, and brain imaging abnormalities

  Inheritance: AD Classification: STRONG, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -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 VariationId 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 the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 87 AD,Unknown,AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000376476.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
There are no transcript annotations for this variant.

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NPPA	ENST00000376476.1	TSL:3	c.-57G>A		5_prime_UTR	Exon 1 of 3	ENSP00000365659.1
	CLCN6	ENST00000400892.3	TSL:3	n.*2495C>T		downstream_gene	N/A	ENSP00000496938.1

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

African (AFR) AF: 0.00384 AC: 18 AN: 4684

American (AMR) AF: 0.0164 AC: 118 AN: 7174

Ashkenazi Jewish (ASJ) AF: 0.00978 AC: 36 AN: 3680

East Asian (EAS) AF: 0.00 AC: 0 AN: 6648

South Asian (SAS) AF: 0.00830 AC: 240 AN: 28902

European-Finnish (FIN) AF: 0.0681 AC: 454 AN: 6662

Middle Eastern (MID) AF: 0.00361 AC: 2 AN: 554

European-Non Finnish (NFE) AF: 0.0386 AC: 3383 AN: 87730

Other (OTH) AF: 0.0324 AC: 245 AN: 7558

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

African (AFR) AF: 0.00596 AC: 248 AN: 41588

American (AMR) AF: 0.0179 AC: 274 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.00720 AC: 25 AN: 3472

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5184

South Asian (SAS) AF: 0.00622 AC: 30 AN: 4826

European-Finnish (FIN) AF: 0.0627 AC: 666 AN: 10622

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.0389 AC: 2648 AN: 68034

Other (OTH) AF: 0.0246 AC: 52 AN: 2114

Alfa AF: 0.0325 Hom.: 45

Bravo AF: 0.0208

Asia WGS AF: 0.00404 AC: 14 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	14
DANN	Benign	0.62
PhyloP100		1.2
PromoterAI		0.0075	Neutral
Mutation Taster		=300/0	polymorphism

Splicing

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

Other links and lift over

dbSNP: rs17376426; hg19: chr1-11908167;