rs198370

Variant names:

• chr1-11846924-T-C
• rs198370
• NM_006172.4:c.450+189A>G

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_006172.4(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 NM_006172.4 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.299
• Publications: 7 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]

NPPA-AS1 (HGNC:37635): (NPPA antisense RNA 1)

ACMG classification

Our verdict: Benign. The variant received -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 VariationId 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006172.4. 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
	NPPA	NM_006172.4	MANE Select	c.450+189A>G		intron	N/A	NP_006163.1	P01160
	NPPA-AS1	NR_037806.1		n.1480-510T>C		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NPPA	ENST00000376480.7	TSL:1 MANE Select	c.450+189A>G		intron	N/A	ENSP00000365663.3	P01160
	CLCN6	ENST00000446542.5	TSL:1	n.782-510T>C		intron	N/A
	NPPA	ENST00000376476.1	TSL:3	c.300+189A>G		intron	N/A	ENSP00000365659.1	B0ZBE8

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

African (AFR) AF: 0.299 AC: 12038 AN: 40212

American (AMR) AF: 0.0916 AC: 1354 AN: 14778

Ashkenazi Jewish (ASJ) AF: 0.0524 AC: 180 AN: 3438

East Asian (EAS) AF: 0.00750 AC: 33 AN: 4402

South Asian (SAS) AF: 0.106 AC: 458 AN: 4302

European-Finnish (FIN) AF: 0.0403 AC: 383 AN: 9494

Middle Eastern (MID) AF: 0.169 AC: 49 AN: 290

European-Non Finnish (NFE) AF: 0.0877 AC: 5859 AN: 66778

Other (OTH) AF: 0.141 AC: 289 AN: 2054

Alfa AF: 0.108 Hom.: 1709

Bravo AF: 0.149

Asia WGS AF: 0.0600 AC: 207 AN: 3476

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	-0.87
CADD	Benign	6.8
DANN	Benign	0.80
PhyloP100		0.30
Mutation Taster		=100/0	polymorphism (auto)

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: rs198370; hg19: chr1-11906981;