NM_003995.4:c.2713-172C>G

Variant names:

• chr9-35808337-C-G
• rs3763631
• NM_003995.4:c.2713-172C>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_003995.4(NPR2):​c.2713-172C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.289 in 1,518,044 control chromosomes in the GnomAD database, including 66,506 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.23 (4932 hom., cov: 32)
  • Exomes 𝑓: 0.30 (61574 hom.)
• Consequence: NPR2 NM_003995.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.24
• Publications: 23 publications found

Genes affected

NPR2 (HGNC:7944): (natriuretic peptide receptor 2) This gene encodes natriuretic peptide receptor B, one of two integral membrane receptors for natriuretic peptides. Both NPR1 and NPR2 contain five functional domains: an extracellular ligand-binding domain, a single membrane-spanning region, and intracellularly a protein kinase homology domain, a helical hinge region involved in oligomerization, and a carboxyl-terminal guanylyl cyclase catalytic domain. The protein is the primary receptor for C-type natriuretic peptide (CNP), which upon ligand binding exhibits greatly increased guanylyl cyclase activity. Mutations in this gene are the cause of acromesomelic dysplasia Maroteaux type. [provided by RefSeq, Jul 2008]

SPAG8 (HGNC:14105): (sperm associated antigen 8) The correlation of anti-sperm antibodies with cases of unexplained infertility implicates a role for these antibodies in blocking fertilization. Improved diagnosis and treatment of immunologic infertility, as well as identification of proteins for targeted contraception, are dependent on the identification and characterization of relevant sperm antigens. The protein encoded by this gene is recognized by sperm agglutinating antibodies from an infertile woman. This protein is localized in germ cells of the testis at all stages of spermatogenesis and is localized to the acrosomal region of mature spermatozoa. This protein interacts with ACT (activator of CREM in testis) and may play a role in CREM (cAMP response element modulator)-ACT-mediated gene transcription during spermatogenesis. This protein may also play a role in spermatogenesis by regulating microtubule formation and cell division. Alternatively spliced variants that encode different protein isoforms have been described but the full-length sequences of only two have been determined. [provided by RefSeq, Jul 2012]

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BP6: Variant 9-35808337-C-G is Benign according to our data. Variant chr9-35808337-C-G is described in ClinVar as [Benign]. Clinvar id is 1282017.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.303 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NPR2	NM_003995.4	c.2713-172C>G		intron_variant	Intron 18 of 21	ENST00000342694.7	NP_003986.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NPR2	ENST00000342694.7	c.2713-172C>G		intron_variant	Intron 18 of 21	1	NM_003995.4	ENSP00000341083.2

Frequencies

GnomAD3 genomes AF: 0.231 AC: 35147 AN: 152012 Hom.: 4930 Cov.: 32

Gnomad AFR AF: 0.0713

Gnomad AMI AF: 0.477

Gnomad AMR AF: 0.279

Gnomad ASJ AF: 0.193

Gnomad EAS AF: 0.154

Gnomad SAS AF: 0.236

Gnomad FIN AF: 0.325

Gnomad MID AF: 0.225

Gnomad NFE AF: 0.307

Gnomad OTH AF: 0.260

GnomAD2 exomes AF: 0.265 AC: 63791 AN: 241106 AF XY: 0.267

Gnomad AFR exome AF: 0.0697

Gnomad AMR exome AF: 0.285

Gnomad ASJ exome AF: 0.196

Gnomad EAS exome AF: 0.142

Gnomad FIN exome AF: 0.309

Gnomad NFE exome AF: 0.311

Gnomad OTH exome AF: 0.266

GnomAD4 exome AF: 0.295 AC: 403288 AN: 1365914 Hom.: 61574 Cov.: 21 AF XY: 0.294 AC XY: 201246 AN XY: 684642

African (AFR) AF: 0.0637 AC: 2008 AN: 31504

American (AMR) AF: 0.283 AC: 12372 AN: 43684

Ashkenazi Jewish (ASJ) AF: 0.195 AC: 4977 AN: 25502

East Asian (EAS) AF: 0.187 AC: 7338 AN: 39232

South Asian (SAS) AF: 0.243 AC: 20434 AN: 84072

European-Finnish (FIN) AF: 0.304 AC: 16184 AN: 53162

Middle Eastern (MID) AF: 0.208 AC: 1164 AN: 5586

European-Non Finnish (NFE) AF: 0.315 AC: 323325 AN: 1025930

Other (OTH) AF: 0.271 AC: 15486 AN: 57242

GnomAD4 genome AF: 0.231 AC: 35158 AN: 152130 Hom.: 4932 Cov.: 32 AF XY: 0.233 AC XY: 17295 AN XY: 74358

African (AFR) AF: 0.0711 AC: 2953 AN: 41504

American (AMR) AF: 0.279 AC: 4262 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.193 AC: 670 AN: 3472

East Asian (EAS) AF: 0.154 AC: 801 AN: 5186

South Asian (SAS) AF: 0.236 AC: 1135 AN: 4818

European-Finnish (FIN) AF: 0.325 AC: 3428 AN: 10560

Middle Eastern (MID) AF: 0.231 AC: 68 AN: 294

European-Non Finnish (NFE) AF: 0.307 AC: 20848 AN: 67972

Other (OTH) AF: 0.264 AC: 558 AN: 2114

Alfa AF: 0.199 Hom.: 648

Bravo AF: 0.220

Asia WGS AF: 0.239 AC: 831 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Nov 12, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	5.8
DANN	Benign	0.77
PhyloP100		-1.2
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: rs3763631; hg19: chr9-35808334; COSMIC: COSV52414358; COSMIC: COSV52414358;