1-11846924-T-C

Position:

• chr1-11846924-T-C

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The ENST00000376480.7(NPPA):​c.450+189A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.141 in 146,654 control chromosomes in the GnomAD database, including 2,251 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency: Genomes: 𝑓 0.14 (2251 hom., cov: 29)
• Consequence: NPPA ENST00000376480.7 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.299

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]

NPPA-AS1 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BP6: Variant 1-11846924-T-C is Benign according to our data. Variant chr1-11846924-T-C is described in ClinVar as [Benign]. Clinvar id is 1296343.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.295 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NPPA	NM_006172.4	c.450+189A>G		intron_variant		ENST00000376480.7	NP_006163.1
NPPA-AS1	NR_037806.1	n.1480-510T>C		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NPPA	ENST00000376480.7	c.450+189A>G		intron_variant		1	NM_006172.4	ENSP00000365663	P1
CLCN6	ENST00000446542.5	n.782-510T>C		intron_variant, non_coding_transcript_variant		1
NPPA	ENST00000376476.1	c.300+189A>G		intron_variant		3		ENSP00000365659
CLCN6	ENST00000400892.3	c.*1962-653T>C		intron_variant, NMD_transcript_variant		3		ENSP00000496938

Frequencies

GnomAD3 genomes AF: 0.141 AC: 20718 AN: 146522 Hom.: 2250 Cov.: 29

Gnomad AFR AF: 0.300

Gnomad AMI AF: 0.0993

Gnomad AMR AF: 0.0918

Gnomad ASJ AF: 0.0524

Gnomad EAS AF: 0.00748

Gnomad SAS AF: 0.107

Gnomad FIN AF: 0.0403

Gnomad MID AF: 0.160

Gnomad NFE AF: 0.0878

Gnomad OTH AF: 0.142

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.141 AC: 20733 AN: 146654 Hom.: 2251 Cov.: 29 AF XY: 0.139 AC XY: 9906 AN XY: 71452

Gnomad4 AFR AF: 0.299

Gnomad4 AMR AF: 0.0916

Gnomad4 ASJ AF: 0.0524

Gnomad4 EAS AF: 0.00750

Gnomad4 SAS AF: 0.106

Gnomad4 FIN AF: 0.0403

Gnomad4 NFE AF: 0.0877

Gnomad4 OTH AF: 0.141

Alfa AF: 0.132 Hom.: 212

Bravo AF: 0.149

Asia WGS AF: 0.0600 AC: 207 AN: 3476

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

Sep 04, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	6.8
DANN	Benign	0.80

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

Publications

LitVar

Other links and lift over

dbSNP: rs198370; hg19: chr1-11906981;