6-3076825-T-C

Variant names:

• chr6-3076825-T-C
• rs1268713212
• NM_001354930.2:c.2T>C

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PVS1_Supporting PM2

The NM_001354930.2(RIPK1):​c.2T>C​(p.Met1?) variant causes a start lost change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,324 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 27)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: RIPK1 NM_001354930.2 start_lost
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.594
• Publications: 0 publications found

Genes affected

RIPK1 (HGNC:10019): (receptor interacting serine/threonine kinase 1) This gene encodes a member of the receptor-interacting protein (RIP) family of serine/threonine protein kinases. The encoded protein plays a role in inflammation and cell death in response to tissue damage, pathogen recognition, and as part of developmental regulation. RIPK1/RIPK3 kinase-mediated necrosis is referred to as necroptosis. Genetic disruption of this gene in mice results in death shortly after birth. [provided by RefSeq, Aug 2017]

RIPK1 Gene-Disease associations (from GenCC):

• immunodeficiency 57

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: ClinGen, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• autoinflammation with episodic fever and lymphadenopathy

  Inheritance: AD Classification: STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics
• immune dysregulation-inflammatory bowel disease-arthritis-recurrent infections-lymphopenia syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PVS1: Start lost variant, no pathogenic variants between lost start and next in-frame start position. Next in-frame start position is after 5 codons. Genomic position: 3076836. Lost 0.006 part of the original CDS.
• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001354930.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RIPK1	NM_001354930.2	MANE Select	c.2T>C	p.Met1?	start_lost	Exon 2 of 11	NP_001341859.1	Q13546-1
	RIPK1	NM_003804.6		c.2T>C	p.Met1?	start_lost	Exon 2 of 11	NP_003795.2	Q13546-1
	RIPK1	NM_001354931.2		c.2T>C	p.Met1?	start_lost	Exon 2 of 10	NP_001341860.1	Q13546-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RIPK1	ENST00000259808.9	TSL:5 MANE Select	c.2T>C	p.Met1?	start_lost	Exon 2 of 11	ENSP00000259808.3	Q13546-1
	RIPK1	ENST00000380409.3	TSL:1	c.2T>C	p.Met1?	start_lost	Exon 2 of 10	ENSP00000369773.3	Q13546-2
	RIPK1	ENST00000967583.1		c.2T>C	p.Met1?	start_lost	Exon 2 of 12	ENSP00000637642.1

Frequencies

GnomAD3 genomes Cov.: 27

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461324 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 726942

African (AFR) AF: 0.00 AC: 0 AN: 33456

American (AMR) AF: 0.00 AC: 0 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26124

East Asian (EAS) AF: 0.00 AC: 0 AN: 39674

South Asian (SAS) AF: 0.00 AC: 0 AN: 86194

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53378

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5672

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1111764

Other (OTH) AF: 0.00 AC: 0 AN: 60348

GnomAD4 genome Cov.: 27

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.096	T
BayesDel_noAF	Benign	-0.38
CADD	Benign	8.1
DANN	Benign	0.95
DEOGEN2	Benign	0.14	T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.080	N
LIST_S2	Uncertain	0.90	D
M_CAP	Benign	0.053	D
MetaRNN	Uncertain	0.73	D
MetaSVM	Benign	-1.0	T
PhyloP100		-0.59
PROVEAN	Benign	-0.35	N
REVEL	Benign	0.23
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.031	D
Polyphen		0.0010	B
Vest4		0.21
MutPred		0.95		Gain of catalytic residue at M1 (P = 0.0233)
MVP		0.70
ClinPred		0.89	D
GERP RS		-4.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.35
gMVP		0.61
Mutation Taster		=135/65	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

Other links and lift over

dbSNP: rs1268713212; hg19: chr6-3077059;