1-11846911-G-GCC

Variant names:

• chr1-11846911-G-GCC
• rs67372226
• NM_006172.4:c.450+200_450+201dupGG

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 0P and 0B.

The NM_006172.4(NPPA):​c.450+200_450+201dupGG 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 0.00058 (0 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: Uncertain_significance. The variant received 0 ACMG points.

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+200_450+201dupGG		intron	N/A	NP_006163.1	P01160
	NPPA-AS1	NR_037806.1		n.1480-514_1480-513dupCC		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+202insGG		intron	N/A	ENSP00000365663.3	P01160
	CLCN6	ENST00000446542.5	TSL:1	n.782-523_782-522insCC		intron	N/A
	NPPA	ENST00000376476.1	TSL:3	c.300+201_300+202insGG		intron	N/A	ENSP00000365659.1	B0ZBE8

Frequencies

GnomAD3 genomes AF: 0.000583 AC: 81 AN: 138952 Hom.: 0 Cov.: 0

Gnomad AFR AF: 0.000465

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000723

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00165

Gnomad FIN AF: 0.000531

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000764

Gnomad OTH AF: 0.00104

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

GnomAD4 genome AF: 0.000583 AC: 81 AN: 138994 Hom.: 0 Cov.: 0 AF XY: 0.000464 AC XY: 31 AN XY: 66850

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.000464 AC: 18 AN: 38806

American (AMR) AF: 0.0000723 AC: 1 AN: 13832

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3342

East Asian (EAS) AF: 0.00 AC: 0 AN: 4018

South Asian (SAS) AF: 0.00166 AC: 7 AN: 4224

European-Finnish (FIN) AF: 0.000531 AC: 4 AN: 7534

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 282

European-Non Finnish (NFE) AF: 0.000764 AC: 49 AN: 64156

Other (OTH) AF: 0.00103 AC: 2 AN: 1946

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.00000000000000155431), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.000538 Hom.: 179

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.17

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs67372226; hg19: chr1-11906968;