rs61757261

Variant names:

• chr1-11847373-T-G
• rs61757261
• NM_006172.4:c.190A>C

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The ENST00000376480.7(NPPA):​c.190A>C​(p.Ser64Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00247 in 1,614,004 control chromosomes in the GnomAD database, including 11 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0016 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0026 (11 hom.)
• Consequence: NPPA ENST00000376480.7 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts P:1 B:9
• Conservation: PhyloP100: 1.04
• 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]

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

ENSG00000275915 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.005454272).
• BP6: Variant 1-11847373-T-G is Benign according to our data. Variant chr1-11847373-T-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 126847.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Homozygotes in GnomAdExome4 at 11 AD,Unknown,AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000376480.7. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NPPA	NM_006172.4	MANE Select	c.190A>C	p.Ser64Arg	missense	Exon 2 of 3	NP_006163.1
	NPPA-AS1	NR_037806.1		n.1480-61T>G		intron	N/A

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NPPA	ENST00000376480.7	TSL:1 MANE Select	c.190A>C	p.Ser64Arg	missense	Exon 2 of 3	ENSP00000365663.3
	CLCN6	ENST00000446542.5	TSL:1	n.782-61T>G		intron	N/A
	NPPA	ENST00000376476.1	TSL:3	c.40A>C	p.Ser14Arg	missense	Exon 2 of 3	ENSP00000365659.1

Frequencies

GnomAD3 genomes AF: 0.00166 AC: 253 AN: 152222 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000458

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00183

Gnomad ASJ AF: 0.00720

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000621

Gnomad FIN AF: 0.000283

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.00245

Gnomad OTH AF: 0.00287

GnomAD2 exomes AF: 0.00202 AC: 504 AN: 249756 AF XY: 0.00201

Gnomad AFR exome AF: 0.000504

Gnomad AMR exome AF: 0.00168

Gnomad ASJ exome AF: 0.00547

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000277

Gnomad NFE exome AF: 0.00290

Gnomad OTH exome AF: 0.00295

GnomAD4 exome AF: 0.00256 AC: 3740 AN: 1461664 Hom.: 11 Cov.: 32 AF XY: 0.00257 AC XY: 1870 AN XY: 727114

African (AFR) AF: 0.000598 AC: 20 AN: 33472

American (AMR) AF: 0.00190 AC: 85 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.00616 AC: 161 AN: 26134

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39700

South Asian (SAS) AF: 0.00101 AC: 87 AN: 86256

European-Finnish (FIN) AF: 0.000638 AC: 34 AN: 53314

Middle Eastern (MID) AF: 0.00225 AC: 13 AN: 5768

European-Non Finnish (NFE) AF: 0.00288 AC: 3201 AN: 1111926

Other (OTH) AF: 0.00229 AC: 138 AN: 60378

GnomAD4 genome AF: 0.00165 AC: 251 AN: 152340 Hom.: 0 Cov.: 32 AF XY: 0.00153 AC XY: 114 AN XY: 74494

African (AFR) AF: 0.000457 AC: 19 AN: 41588

American (AMR) AF: 0.00183 AC: 28 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.00720 AC: 25 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.000621 AC: 3 AN: 4830

European-Finnish (FIN) AF: 0.000283 AC: 3 AN: 10618

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.00245 AC: 167 AN: 68038

Other (OTH) AF: 0.00237 AC: 5 AN: 2112

Alfa AF: 0.00255 Hom.: 3

Bravo AF: 0.00164

TwinsUK AF: 0.00297 AC: 11

ALSPAC AF: 0.00182 AC: 7

ESP6500AA AF: 0.000454 AC: 2

ESP6500EA AF: 0.00279 AC: 24

ExAC AF: 0.00189 AC: 230

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00322

EpiControl AF: 0.00320

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
1	-	1	Atrial fibrillation, familial, 6 (2)
-	-	2	not specified (2)
-	-	1	Atrial fibrillation, familial, 6;C3810401:Atrial standstill 2 (1)
-	-	1	NPPA-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.36	T
BayesDel_noAF	Benign	-0.29
CADD	Benign	7.7
DANN	Benign	0.78
DEOGEN2	Benign	0.011	T
Eigen	Benign	-0.72
Eigen_PC	Benign	-0.75
FATHMM_MKL	Benign	0.068	N
LIST_S2	Benign	0.59	T
M_CAP	Benign	0.014	T
MetaRNN	Benign	0.0055	T
MetaSVM	Benign	-1.0	T
PhyloP100		1.0
PrimateAI	Benign	0.32	T
PROVEAN	Benign	-0.59	N
REVEL	Benign	0.19
Sift	Benign	0.46	T
Sift4G	Benign	0.57	T
Vest4		0.61
MutPred		0.43		Loss of glycosylation at S64 (P = 0.0239)
MVP		0.67
MPC		0.023
ClinPred		0.014	T
GERP RS		3.5
PromoterAI		-0.0045	Neutral
gMVP		0.19
Mutation Taster		=96/4	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs61757261; hg19: chr1-11907430;