1-11846911-GCC-GCCC

Variant names:

• chr1-11846911-G-GC
• rs67372226
• NM_006172.4:c.450+201dupG

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BS1 BS2

The NM_006172.4(NPPA):​c.450+201dupG variant causes a intron change involving the alteration of a non-conserved nucleotide. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.0081 (8 hom., cov: 0)
• Consequence: NPPA NM_006172.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.174
• Publications: 0 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 -8 ACMG points.

• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00809 (1123/138874) while in subpopulation AFR AF = 0.0192 (744/38730). AF 95% confidence interval is 0.0181. There are 8 homozygotes in GnomAd4. There are 540 alleles in the male GnomAd4 subpopulation. Median coverage is 0. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 8 AD,Unknown,AR gene

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+201dupG		intron	N/A	NP_006163.1	P01160
	NPPA-AS1	NR_037806.1		n.1480-513dupC		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+201_450+202insG		intron	N/A	ENSP00000365663.3	P01160
	CLCN6	ENST00000446542.5	TSL:1	n.782-523_782-522insC		intron	N/A
	NPPA	ENST00000376476.1	TSL:3	c.300+201_300+202insG		intron	N/A	ENSP00000365659.1	B0ZBE8

Frequencies

GnomAD3 genomes AF: 0.00809 AC: 1123 AN: 138830 Hom.: 8 Cov.: 0

Gnomad AFR AF: 0.0192

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00753

Gnomad ASJ AF: 0.00269

Gnomad EAS AF: 0.0144

Gnomad SAS AF: 0.00567

Gnomad FIN AF: 0.000398

Gnomad MID AF: 0.00645

Gnomad NFE AF: 0.00256

Gnomad OTH AF: 0.00830

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

GnomAD4 genome AF: 0.00809 AC: 1123 AN: 138874 Hom.: 8 Cov.: 0 AF XY: 0.00809 AC XY: 540 AN XY: 66786

African (AFR) AF: 0.0192 AC: 744 AN: 38730

American (AMR) AF: 0.00760 AC: 105 AN: 13816

Ashkenazi Jewish (ASJ) AF: 0.00269 AC: 9 AN: 3342

East Asian (EAS) AF: 0.0145 AC: 58 AN: 4012

South Asian (SAS) AF: 0.00545 AC: 23 AN: 4222

European-Finnish (FIN) AF: 0.000398 AC: 3 AN: 7532

Middle Eastern (MID) AF: 0.00355 AC: 1 AN: 282

European-Non Finnish (NFE) AF: 0.00256 AC: 164 AN: 64140

Other (OTH) AF: 0.00823 AC: 16 AN: 1944

Alfa AF: 0.00247 Hom.: 179

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.17
Mutation Taster		=100/0	polymorphism

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: rs67372226; hg19: chr1-11906968;