rs5064

Variant names:

• chr1-11847546-G-A
• rs5064
• NM_006172.4:c.123+16C>T

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 21 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]

ENSG00000275915 (HGNC:):

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

ACMG classification

Our verdict: Benign. The variant received -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 VariationId is 36663.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.28 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.123+16C>T		intron	N/A	NP_006163.1	P01160
	NPPA-AS1	NR_037806.1		n.1592G>A		non_coding_transcript_exon	Exon 4 of 4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NPPA	ENST00000376480.7	TSL:1 MANE Select	c.123+16C>T		intron	N/A	ENSP00000365663.3	P01160
	CLCN6	ENST00000446542.5	TSL:1	n.894G>A		non_coding_transcript_exon	Exon 4 of 4
	NPPA	ENST00000376476.1	TSL:3	c.-27-107C>T		intron	N/A	ENSP00000365659.1	B0ZBE8

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

GnomAD2 exomes AF: 0.0857 AC: 21539 AN: 251394 AF XY: 0.0840

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 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

African (AFR) AF: 0.292 AC: 9764 AN: 33476

American (AMR) AF: 0.0615 AC: 2749 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0617 AC: 1613 AN: 26136

East Asian (EAS) AF: 0.00461 AC: 183 AN: 39700

South Asian (SAS) AF: 0.110 AC: 9476 AN: 86252

European-Finnish (FIN) AF: 0.0428 AC: 2285 AN: 53412

Middle Eastern (MID) AF: 0.135 AC: 776 AN: 5768

European-Non Finnish (NFE) AF: 0.0859 AC: 95490 AN: 1111954

Other (OTH) AF: 0.0928 AC: 5605 AN: 60396

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

African (AFR) AF: 0.284 AC: 11769 AN: 41466

American (AMR) AF: 0.0893 AC: 1367 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.0518 AC: 180 AN: 3472

East Asian (EAS) AF: 0.00677 AC: 35 AN: 5172

South Asian (SAS) AF: 0.0959 AC: 463 AN: 4828

European-Finnish (FIN) AF: 0.0405 AC: 430 AN: 10610

Middle Eastern (MID) AF: 0.160 AC: 47 AN: 294

European-Non Finnish (NFE) AF: 0.0863 AC: 5868 AN: 68018

Other (OTH) AF: 0.135 AC: 285 AN: 2116

Alfa AF: 0.130 Hom.: 412

Bravo AF: 0.145

Asia WGS AF: 0.0540 AC: 187 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Atrial fibrillation, familial, 6 (1)
-	-	1	Cardiac arrhythmia (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	1.9
DANN	Benign	0.75
PhyloP100		-0.52
PromoterAI		-0.021	Neutral
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: rs5064; hg19: chr1-11907603; COSMIC: COSV56739762; COSMIC: COSV56739762;