rs5064

Positions:

• chr1-11847546-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_006172.4(NPPA):​c.123+16C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.092 in 1,614,006 control chromosomes in the GnomAD database, including 8,829 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.13 (2084 hom., cov: 32)
  • Exomes 𝑓: 0.088 (6745 hom.)
• Consequence: NPPA NM_006172.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.517

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:):

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP6: Variant 1-11847546-G-A is Benign according to our data. Variant chr1-11847546-G-A is described in ClinVar as [Benign]. Clinvar id is 36663.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-11847546-G-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.28 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NPPA	NM_006172.4	c.123+16C>T		intron_variant		ENST00000376480.7	NP_006163.1
NPPA-AS1	NR_037806.1	n.1592G>A		non_coding_transcript_exon_variant	4/4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NPPA	ENST00000376480.7	c.123+16C>T		intron_variant		1	NM_006172.4	ENSP00000365663.3

Frequencies

GnomAD3 genomes AF: 0.135 AC: 20525 AN: 152070 Hom.: 2084 Cov.: 32

Gnomad AFR AF: 0.284

Gnomad AMI AF: 0.0987

Gnomad AMR AF: 0.0895

Gnomad ASJ AF: 0.0518

Gnomad EAS AF: 0.00675

Gnomad SAS AF: 0.0960

Gnomad FIN AF: 0.0405

Gnomad MID AF: 0.152

Gnomad NFE AF: 0.0863

Gnomad OTH AF: 0.136

GnomAD3 exomes AF: 0.0857 AC: 21539 AN: 251394 Hom.: 1399 AF XY: 0.0840 AC XY: 11415 AN XY: 135884

Gnomad AFR exome AF: 0.290

Gnomad AMR exome AF: 0.0586

Gnomad ASJ exome AF: 0.0605

Gnomad EAS exome AF: 0.00772

Gnomad SAS exome AF: 0.110

Gnomad FIN exome AF: 0.0437

Gnomad NFE exome AF: 0.0808

Gnomad OTH exome AF: 0.0875

GnomAD4 exome AF: 0.0875 AC: 127941 AN: 1461818 Hom.: 6745 Cov.: 33 AF XY: 0.0883 AC XY: 64213 AN XY: 727202

Gnomad4 AFR exome AF: 0.292

Gnomad4 AMR exome AF: 0.0615

Gnomad4 ASJ exome AF: 0.0617

Gnomad4 EAS exome AF: 0.00461

Gnomad4 SAS exome AF: 0.110

Gnomad4 FIN exome AF: 0.0428

Gnomad4 NFE exome AF: 0.0859

Gnomad4 OTH exome AF: 0.0928

GnomAD4 genome AF: 0.135 AC: 20534 AN: 152188 Hom.: 2084 Cov.: 32 AF XY: 0.132 AC XY: 9826 AN XY: 74414

Gnomad4 AFR AF: 0.284

Gnomad4 AMR AF: 0.0893

Gnomad4 ASJ AF: 0.0518

Gnomad4 EAS AF: 0.00677

Gnomad4 SAS AF: 0.0959

Gnomad4 FIN AF: 0.0405

Gnomad4 NFE AF: 0.0863

Gnomad4 OTH AF: 0.135

Alfa AF: 0.126 Hom.: 373

Bravo AF: 0.145

Asia WGS AF: 0.0540 AC: 187 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 23, 2019	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

-

- -

Atrial fibrillation, familial, 6 Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

Cardiac arrhythmia Benign:1

Benign, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Aug 18, 2011

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	1.9
DANN	Benign	0.75

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: rs5064; hg19: chr1-11907603; COSMIC: COSV56739762; COSMIC: COSV56739762;