chr1-11846856-C-G

Variant names:

• chr1-11846856-C-G
• rs198368
• NM_006172.4:c.450+257G>C

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+257G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.136 in 151,000 control chromosomes in the GnomAD database, including 2,137 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency: Genomes: 𝑓 0.14 (2137 hom., cov: 28)
• Consequence: NPPA NM_006172.4 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -2.31

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=-1.07).
• BP6: Variant 1-11846856-C-G is Benign according to our data. Variant chr1-11846856-C-G is described in ClinVar as [Benign]. Clinvar id is 1182455.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.285 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NPPA	NM_006172.4	c.450+257G>C		intron_variant	Intron 2 of 2	ENST00000376480.7	NP_006163.1
NPPA-AS1	NR_037806.1	n.1480-578C>G		intron_variant	Intron 3 of 3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NPPA	ENST00000376480.7	c.450+257G>C		intron_variant	Intron 2 of 2	1	NM_006172.4	ENSP00000365663.3
CLCN6	ENST00000446542.5	n.782-578C>G		intron_variant	Intron 3 of 3	1
NPPA	ENST00000376476.1	c.300+257G>C		intron_variant	Intron 2 of 2	3		ENSP00000365659.1
CLCN6	ENST00000400892.3	n.*1962-721C>G		intron_variant	Intron 26 of 26	3		ENSP00000496938.1

Frequencies

GnomAD3 genomes AF: 0.136 AC: 20471 AN: 150884 Hom.: 2136 Cov.: 28

Gnomad AFR AF: 0.290

Gnomad AMI AF: 0.0991

Gnomad AMR AF: 0.0883

Gnomad ASJ AF: 0.0514

Gnomad EAS AF: 0.00659

Gnomad SAS AF: 0.0943

Gnomad FIN AF: 0.0383

Gnomad MID AF: 0.152

Gnomad NFE AF: 0.0862

Gnomad OTH AF: 0.136

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

GnomAD4 genome AF: 0.136 AC: 20486 AN: 151000 Hom.: 2137 Cov.: 28 AF XY: 0.133 AC XY: 9795 AN XY: 73786

Gnomad4 AFR AF: 0.289 AC: 0.289403 AN: 0.289403

Gnomad4 AMR AF: 0.0882 AC: 0.088185 AN: 0.088185

Gnomad4 ASJ AF: 0.0514 AC: 0.0514451 AN: 0.0514451

Gnomad4 EAS AF: 0.00660 AC: 0.00660451 AN: 0.00660451

Gnomad4 SAS AF: 0.0942 AC: 0.0942059 AN: 0.0942059

Gnomad4 FIN AF: 0.0383 AC: 0.0382917 AN: 0.0382917

Gnomad4 NFE AF: 0.0862 AC: 0.0861983 AN: 0.0861983

Gnomad4 OTH AF: 0.135 AC: 0.134762 AN: 0.134762

Alfa AF: 0.0330 Hom.: 23

Bravo AF: 0.148

Asia WGS AF: 0.0580 AC: 201 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Sep 04, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.1
CADD	Benign	0.11
DANN	Benign	0.28
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

Publications

LitVar

Other links and lift over

dbSNP: rs198368; hg19: chr1-11906913;