9-35808277-C-T

Variant names:

• chr9-35808277-C-T
• rs116570800
• ENST00000340291.6:c.1402G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_003995.4(NPR2):​c.2713-232C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000916 in 1,613,852 control chromosomes in the GnomAD database, including 10 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0044 (7 hom., cov: 32)
  • Exomes 𝑓: 0.00056 (3 hom.)
• Consequence: NPR2 NM_003995.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.245
• Publications: 5 publications found

Genes affected

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]

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]

NPR2 Gene-Disease associations (from GenCC):

• acromesomelic dysplasia 1, Maroteaux type

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics
• short stature with nonspecific skeletal abnormalities 1

  Inheritance: AD Classification: STRONG, MODERATE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
• tall stature-scoliosis-macrodactyly of the great toes syndrome

  Inheritance: AD Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), Orphanet

ACMG classification

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

• BP4: Computational evidence support a benign effect (MetaRNN=0.004222393).
• BP6: Variant 9-35808277-C-T is Benign according to our data. Variant chr9-35808277-C-T is described in ClinVar as [Benign]. Clinvar id is 707361.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00437 (665/152248) while in subpopulation AFR AF = 0.0152 (632/41548). AF 95% confidence interval is 0.0142. There are 7 homozygotes in GnomAd4. There are 315 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 7 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NPR2	NM_003995.4	c.2713-232C>T		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.2713-232C>T		intron_variant	Intron 18 of 21	1	NM_003995.4	ENSP00000341083.2

Frequencies

GnomAD3 genomes AF: 0.00436 AC: 663 AN: 152130 Hom.: 7 Cov.: 32

Gnomad AFR AF: 0.0152

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00111

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000415

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000118

Gnomad OTH AF: 0.00336

GnomAD2 exomes AF: 0.00119 AC: 298 AN: 251440 AF XY: 0.000824

Gnomad AFR exome AF: 0.0155

Gnomad AMR exome AF: 0.000578

Gnomad ASJ exome AF: 0.0000992

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000141

Gnomad OTH exome AF: 0.000978

GnomAD4 exome AF: 0.000556 AC: 813 AN: 1461604 Hom.: 3 Cov.: 30 AF XY: 0.000477 AC XY: 347 AN XY: 727136

African (AFR) AF: 0.0168 AC: 561 AN: 33468

American (AMR) AF: 0.000671 AC: 30 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0000383 AC: 1 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.0000464 AC: 4 AN: 86252

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53418

Middle Eastern (MID) AF: 0.00191 AC: 11 AN: 5768

European-Non Finnish (NFE) AF: 0.000132 AC: 147 AN: 1111750

Other (OTH) AF: 0.000977 AC: 59 AN: 60390

GnomAD4 genome AF: 0.00437 AC: 665 AN: 152248 Hom.: 7 Cov.: 32 AF XY: 0.00423 AC XY: 315 AN XY: 74438

African (AFR) AF: 0.0152 AC: 632 AN: 41548

American (AMR) AF: 0.00111 AC: 17 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5194

South Asian (SAS) AF: 0.00 AC: 0 AN: 4818

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10608

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

European-Non Finnish (NFE) AF: 0.000118 AC: 8 AN: 68012

Other (OTH) AF: 0.00332 AC: 7 AN: 2108

Alfa AF: 0.00177 Hom.: 4

Bravo AF: 0.00482

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.0159 AC: 70

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00153 AC: 186

Asia WGS AF: 0.00173 AC: 6 AN: 3478

EpiCase AF: 0.000109

EpiControl AF: 0.000296

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Jun 14, 2018

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.63	T
BayesDel_noAF	Benign	-0.67
CADD	Benign	3.3
DANN	Benign	0.61
Eigen	Benign	-0.36
Eigen_PC	Benign	-0.58
FATHMM_MKL	Benign	0.022	N
LIST_S2	Benign	0.31	T
MetaRNN	Benign	0.0042	T
MetaSVM	Benign	-1.0	T
PhyloP100		0.24
PrimateAI	Benign	0.32	T
PROVEAN	Benign	-0.13	N
REVEL	Benign	0.11
Sift	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.14
MutPred		0.56		Gain of sheet (P = 0.0344);
MVP		0.36
MPC		0.26
ClinPred		0.032	T
GERP RS		2.6
gMVP		0.064
Mutation Taster		=98/2	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.13		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: rs116570800; hg19: chr9-35808274; COSMIC: COSV52415588; COSMIC: COSV52415588;