NM_001354930.2:c.2T>C

Variant names:

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

Variant summary

Our verdict is Uncertain significance. Variant got 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

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RIPK1	NM_001354930.2	c.2T>C	p.Met1?	start_lost	Exon 2 of 11	ENST00000259808.9	NP_001341859.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RIPK1	ENST00000259808.9	c.2T>C	p.Met1?	start_lost	Exon 2 of 11	5	NM_001354930.2	ENSP00000259808.3

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

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 27

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

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;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;D
MetaSVM	Benign	-1.0	T
PROVEAN	Benign	-0.35	N;N
REVEL	Benign	0.23
Sift	Pathogenic	0.0	D;D
Sift4G	Uncertain	0.031	D;D
Polyphen		0.0010	B;B
Vest4		0.21
MutPred		0.95		Gain of catalytic residue at M1 (P = 0.0233);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

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: chr6-3077059;