19-55954767-C-T

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BP4_Strong

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 (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R237H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0016 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0026 (11 hom.)
• Consequence: NLRP8 NM_176811.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.0690

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]

ACMG classification

Verdict is Likely_benign. Variant got -4 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.005699873).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NLRP8	NM_176811.2	c.709C>T	p.Arg237Cys	missense_variant	3/10	ENST00000291971.7
NLRP8	NM_001317000.1	c.709C>T	p.Arg237Cys	missense_variant	3/10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NLRP8	ENST00000291971.7	c.709C>T	p.Arg237Cys	missense_variant	3/10	1	NM_176811.2	P2
NLRP8	ENST00000590542.1	c.709C>T	p.Arg237Cys	missense_variant	3/10	1		A2

Frequencies

GnomAD3 genomes AF: 0.00164 AC: 249 AN: 152176 Hom.: 0 Cov.: 32

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.: 0 AF XY: 0.00133 AC XY: 181 AN XY: 135820

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.: 11 Cov.: 31 AF XY: 0.00257 AC XY: 1872 AN XY: 727242

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.: 0 Cov.: 32 AF XY: 0.00138 AC XY: 103 AN XY: 74474

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.: 2

Bravo AF: 0.00159

TwinsUK AF: 0.00378 AC: 14

ALSPAC AF: 0.00234 AC: 9

ESP6500AA AF: 0.00113 AC: 5

ESP6500EA AF: 0.00267 AC: 23

ExAC AF: 0.00128 AC: 156

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

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	T
BayesDel_noAF	Benign	-0.46
Cadd	Benign	12
Dann	Benign	0.70
DEOGEN2	Benign	0.039	T;.
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.6
FATHMM_MKL	Benign	0.0014	N
LIST_S2	Benign	0.31	T;T
M_CAP	Benign	0.011	T
MetaRNN	Benign	0.0057	T;T
MetaSVM	Benign	-0.75	T
MutationAssessor	Benign	-0.34	N;N
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.26	T
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	T
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

Other links and lift over

dbSNP: rs148518241; hg19: chr19-56466133;