8-89780141-T-C

Variant names:

• chr8-89780141-T-C
• NM_003821.6:c.920T>C

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_003821.6(RIPK2):​c.920T>C​(p.Ile307Thr) variant causes a missense change. The variant allele was found at a frequency of 0.000000709 in 1,410,844 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.1e-7 (0 hom.)
• Consequence: RIPK2 NM_003821.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.88

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: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.31211543).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RIPK2	NM_003821.6	c.920T>C	p.Ile307Thr	missense_variant	Exon 7 of 11	ENST00000220751.5	NP_003812.1
RIPK2	NM_001375360.1	c.509T>C	p.Ile170Thr	missense_variant	Exon 6 of 10		NP_001362289.1
RIPK2	XM_011517357.3	c.407T>C	p.Ile136Thr	missense_variant	Exon 5 of 9		XP_011515659.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RIPK2	ENST00000220751.5	c.920T>C	p.Ile307Thr	missense_variant	Exon 7 of 11	1	NM_003821.6	ENSP00000220751.4
RIPK2	ENST00000522965.1	n.*559T>C		non_coding_transcript_exon_variant	Exon 6 of 10	1		ENSP00000429271.1
RIPK2	ENST00000522965.1	n.*559T>C		3_prime_UTR_variant	Exon 6 of 10	1		ENSP00000429271.1
RIPK2	ENST00000518673.1	n.54T>C		non_coding_transcript_exon_variant	Exon 1 of 2	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 7.09e-7 AC: 1 AN: 1410844 Hom.: 0 Cov.: 24 AF XY: 0.00 AC XY: 0 AN XY: 701212

Gnomad4 AFR exome AF: 0.00 AC: 0 AN: 32298

Gnomad4 AMR exome AF: 0.00 AC: 0 AN: 41192

Gnomad4 ASJ exome AF: 0.00 AC: 0 AN: 25204

Gnomad4 EAS exome AF: 0.00 AC: 0 AN: 39170

Gnomad4 SAS exome AF: 0.00 AC: 0 AN: 81010

Gnomad4 FIN exome AF: 0.00 AC: 0 AN: 51922

Gnomad4 NFE exome AF: 0.00 AC: 0 AN: 1076040

Gnomad4 Remaining exome AF: 0.0000171 AC: 1 AN: 58364

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jun 07, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.920T>C (p.I307T) alteration is located in exon 7 (coding exon 7) of the RIPK2 gene. This alteration results from a T to C substitution at nucleotide position 920, causing the isoleucine (I) at amino acid position 307 to be replaced by a threonine (T). 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	Uncertain	0.48
BayesDel_addAF	Uncertain	0.031	T
BayesDel_noAF	Benign	-0.19
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.19	T
Eigen	Benign	0.074
Eigen_PC	Uncertain	0.25
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.79	T
M_CAP	Benign	0.042	D
MetaRNN	Benign	0.31	T
MetaSVM	Benign	-0.51	T
MutationAssessor	Benign	1.0	L
PrimateAI	Uncertain	0.58	T
PROVEAN	Benign	-2.1	N
REVEL	Benign	0.27
Sift	Uncertain	0.0060	D
Sift4G	Uncertain	0.0070	D
Polyphen		0.22	B
Vest4		0.45
MutPred		0.45		Gain of disorder (P = 0.0248);
MVP		0.53
MPC		0.34
ClinPred		0.85	D
GERP RS		5.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.29
gMVP		0.35
Mutation Taster		=35/65	disease causing

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr8-90792369;