Variant 19-55954767-C-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_176811.2(NLRP8):c.709C>T(p.Arg237Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00255 in 1,614,178 control chromosomes in the GnomAD database, including 11 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0016 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0026 ( 11 hom. )

Consequence

NLRP8
NM_176811.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.0690

Variant links:

Genes affected

NLRP8 (HGNC:22940): (NLR family pyrin domain containing 8) This gene encodes a member of the nucleotide-binding oligomerization domain/ leucine rich repeat/ pyrin domain containing (NLRP) subfamily, which belongs to the Nod-like receptor family of proteins. NLRP genes play roles in the mammalian innate immune system through inflammasome formation and activation of caspases. In addition, NLRP genes have been found to function during mammalian reproduction. Consistent with a function during human preimplantation development, this gene is expressed at high levels in oocytes with decreased levels in embryos. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Sep 2016]

NLRP8 links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.005699873).

BS2

High Homozygotes in GnomAdExome4 at 11 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NLRP8	NM_176811.2 linkuse as main transcript	c.709C>T	p.Arg237Cys	missense_variant	3/10	ENST00000291971.7	NP_789781.2	Q86W28-1
NLRP8	NM_001317000.1 linkuse as main transcript	c.709C>T	p.Arg237Cys	missense_variant	3/10		NP_001303929.1	Q86W28-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NLRP8	ENST00000291971.7 linkuse as main transcript	c.709C>T	p.Arg237Cys	missense_variant	3/10	1	NM_176811.2	ENSP00000291971.3		Q86W28-1
NLRP8	ENST00000590542.1 linkuse as main transcript	c.709C>T	p.Arg237Cys	missense_variant	3/10	1		ENSP00000468121.1		Q86W28-2

Frequencies

GnomAD3 genomes

AF:

0.00164

AC:

249

AN:

152176

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000459

Gnomad AMI

AF:

0.00330

Gnomad AMR

AF:

0.000852

Gnomad ASJ

AF:

0.000288

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00217

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00279

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00137

AC:

344

AN:

251320

Hom.:

AF XY:

0.00133

AC XY:

181

AN XY:

135820

show subpopulations

Gnomad AFR exome

AF:

0.000800

Gnomad AMR exome

AF:

0.00119

Gnomad ASJ exome

AF:

0.00129

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00171

Gnomad NFE exome

AF:

0.00205

Gnomad OTH exome

AF:

0.00114

GnomAD4 exome

AF:

0.00265

AC:

3872

AN:

1461884

Hom.:

Cov.:

AF XY:

0.00257

AC XY:

1872

AN XY:

727242

show subpopulations

Gnomad4 AFR exome

AF:

0.000448

Gnomad4 AMR exome

AF:

0.00101

Gnomad4 ASJ exome

AF:

0.000957

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00118

Gnomad4 NFE exome

AF:

0.00319

Gnomad4 OTH exome

AF:

0.00286

GnomAD4 genome

AF:

0.00163

AC:

249

AN:

152294

Hom.:

Cov.:

AF XY:

0.00138

AC XY:

103

AN XY:

74474

show subpopulations

Gnomad4 AFR

AF:

0.000457

Gnomad4 AMR

AF:

0.000850

Gnomad4 ASJ

AF:

0.000288

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00217

Gnomad4 NFE

AF:

0.00279

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.00236

Hom.:

Bravo

AF:

0.00159

TwinsUK

AF:

0.00378

AC:

ALSPAC

AF:

0.00234

AC:

ESP6500AA

AF:

0.00113

AC:

ESP6500EA

AF:

0.00267

AC:

ExAC

AF:

0.00128

AC:

156

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 17, 2023

The c.709C>T (p.R237C) alteration is located in exon 3 (coding exon 3) of the NLRP8 gene. This alteration results from a C to T substitution at nucleotide position 709, causing the arginine (R) at amino acid position 237 to be replaced by a cysteine (C). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.48

BayesDel_noAF

Benign

-0.46

CADD

Benign

DANN

Benign

0.70

DEOGEN2

Benign

0.039

T;.

Eigen

Benign

-1.5

Eigen_PC

Benign

-1.6

FATHMM_MKL

Benign

0.0014

LIST_S2

Benign

0.31

T;T

M_CAP

Benign

0.011

MetaRNN

Benign

0.0057

T;T

MetaSVM

Benign

-0.75

MutationAssessor

Benign

-0.34

N;N

PrimateAI

Benign

0.26

PROVEAN

Benign

0.57

N;.

REVEL

Benign

0.20

Sift

Benign

0.20

T;.

Sift4G

Benign

0.19

T;T

Polyphen

0.0030

B;P

Vest4

0.14

MVP

0.15

MPC

0.19

ClinPred

0.015

GERP RS

-4.1

Varity_R

0.069

gMVP

0.48

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over