8-89769802-A-G

Variant names:

• chr8-89769802-A-G
• rs751621342
• NM_003821.6:c.514A>G

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_003821.6(RIPK2):​c.514A>G​(p.Met172Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000872 in 1,606,082 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/23 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. M172T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000083 (0 hom.)
• Consequence: RIPK2 NM_003821.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.66

Genes affected

RIPK2 (HGNC:10020): (receptor interacting serine/threonine kinase 2) This gene encodes a member of the receptor-interacting protein (RIP) family of serine/threonine protein kinases. The encoded protein contains a C-terminal caspase activation and recruitment domain (CARD), and is a component of signaling complexes in both the innate and adaptive immune pathways. It is a potent activator of NF-kappaB and inducer of apoptosis in response to various stimuli. [provided by RefSeq, Jul 2008]

ACMG classification

Our verdict: Likely_benign. The variant received -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.083164066).
• BS2: High AC in GnomAdExome4 at 12 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RIPK2	NM_003821.6	c.514A>G	p.Met172Val	missense_variant	Exon 4 of 11	ENST00000220751.5	NP_003812.1
RIPK2	XM_011517357.3	c.1A>G	p.Met1?	start_lost	Exon 2 of 9		XP_011515659.1
RIPK2	NM_001375360.1	c.103A>G	p.Met35Val	missense_variant	Exon 3 of 10		NP_001362289.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RIPK2	ENST00000220751.5	c.514A>G	p.Met172Val	missense_variant	Exon 4 of 11	1	NM_003821.6	ENSP00000220751.4
RIPK2	ENST00000522965.1	n.*153A>G		non_coding_transcript_exon_variant	Exon 3 of 10	1		ENSP00000429271.1
RIPK2	ENST00000522965.1	n.*153A>G		3_prime_UTR_variant	Exon 3 of 10	1		ENSP00000429271.1

Frequencies

GnomAD3 genomes AF: 0.0000132 AC: 2 AN: 151896 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000122 AC: 3 AN: 245092 AF XY: 0.0000226

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000270

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000825 AC: 12 AN: 1454186 Hom.: 0 Cov.: 31 AF XY: 0.0000111 AC XY: 8 AN XY: 723416

Gnomad4 AFR exome AF: 0.00 AC: 0 AN: 32878

Gnomad4 AMR exome AF: 0.000162 AC: 7 AN: 43318

Gnomad4 ASJ exome AF: 0.00 AC: 0 AN: 25878

Gnomad4 EAS exome AF: 0.0000254 AC: 1 AN: 39322

Gnomad4 SAS exome AF: 0.00 AC: 0 AN: 85232

Gnomad4 FIN exome AF: 0.00 AC: 0 AN: 53272

Gnomad4 NFE exome AF: 0.00000271 AC: 3 AN: 1108492

Gnomad4 Remaining exome AF: 0.0000167 AC: 1 AN: 60048

GnomAD4 genome AF: 0.0000132 AC: 2 AN: 151896 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74198

Gnomad4 AFR AF: 0.00 AC: 0 AN: 0

Gnomad4 AMR AF: 0.000131 AC: 0.000131492 AN: 0.000131492

Gnomad4 ASJ AF: 0.00 AC: 0 AN: 0

Gnomad4 EAS AF: 0.00 AC: 0 AN: 0

Gnomad4 SAS AF: 0.00 AC: 0 AN: 0

Gnomad4 FIN AF: 0.00 AC: 0 AN: 0

Gnomad4 NFE AF: 0.00 AC: 0 AN: 0

Gnomad4 OTH AF: 0.00 AC: 0 AN: 0

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Aug 01, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.514A>G (p.M172V) alteration is located in exon 4 (coding exon 4) of the RIPK2 gene. This alteration results from a A to G substitution at nucleotide position 514, causing the methionine (M) at amino acid position 172 to be replaced by a valine (V). 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	0.093
BayesDel_addAF	Benign	-0.24	T
BayesDel_noAF	Benign	-0.53
CADD	Benign	8.1
DANN	Benign	0.57
DEOGEN2	Benign	0.17	T
Eigen	Benign	-0.98
Eigen_PC	Benign	-0.81
FATHMM_MKL	Benign	0.56	D
LIST_S2	Benign	0.79	T
M_CAP	Benign	0.0027	T
MetaRNN	Benign	0.083	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.025	N
PrimateAI	Benign	0.40	T
PROVEAN	Benign	-1.1	N
REVEL	Benign	0.049
Sift	Benign	0.55	T
Sift4G	Benign	0.53	T
Polyphen		0.0020	B
Vest4		0.096
MutPred		0.55		Loss of disorder (P = 0.0803);
MVP		0.41
MPC		0.99
ClinPred		0.011	T
GERP RS		-1.6
Varity_R		0.061
gMVP		0.54
Mutation Taster		=64/36	polymorphism

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: rs751621342; hg19: chr8-90782030;