6-3104462-C-T

Variant names:

• chr6-3104462-C-T
• rs10498658
• NM_001354930.2:c.1006+147C>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001354930.2(RIPK1):​c.1006+147C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.189 in 568,022 control chromosomes in the GnomAD database, including 12,350 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.17 (2814 hom., cov: 32)
  • Exomes 𝑓: 0.20 (9536 hom.)
• Consequence: RIPK1 NM_001354930.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.992
• Publications: 14 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: Labcorp Genetics (formerly Invitae), Ambry Genetics
• 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: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.246 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RIPK1	NM_001354930.2	c.1006+147C>T		intron_variant	Intron 8 of 10	ENST00000259808.9	NP_001341859.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RIPK1	ENST00000259808.9	c.1006+147C>T		intron_variant	Intron 8 of 10	5	NM_001354930.2	ENSP00000259808.3

Frequencies

GnomAD3 genomes AF: 0.170 AC: 25869 AN: 151958 Hom.: 2813 Cov.: 32

Gnomad AFR AF: 0.0640

Gnomad AMI AF: 0.221

Gnomad AMR AF: 0.175

Gnomad ASJ AF: 0.227

Gnomad EAS AF: 0.00173

Gnomad SAS AF: 0.0715

Gnomad FIN AF: 0.169

Gnomad MID AF: 0.177

Gnomad NFE AF: 0.249

Gnomad OTH AF: 0.211

GnomAD4 exome AF: 0.196 AC: 81483 AN: 415948 Hom.: 9536 AF XY: 0.192 AC XY: 42221 AN XY: 220166

African (AFR) AF: 0.0653 AC: 755 AN: 11556

American (AMR) AF: 0.157 AC: 2258 AN: 14376

Ashkenazi Jewish (ASJ) AF: 0.226 AC: 2905 AN: 12880

East Asian (EAS) AF: 0.000134 AC: 4 AN: 29790

South Asian (SAS) AF: 0.0728 AC: 2725 AN: 37416

European-Finnish (FIN) AF: 0.171 AC: 5593 AN: 32768

Middle Eastern (MID) AF: 0.214 AC: 478 AN: 2230

European-Non Finnish (NFE) AF: 0.247 AC: 61858 AN: 250862

Other (OTH) AF: 0.204 AC: 4907 AN: 24070

GnomAD4 genome AF: 0.170 AC: 25866 AN: 152074 Hom.: 2814 Cov.: 32 AF XY: 0.165 AC XY: 12278 AN XY: 74344

African (AFR) AF: 0.0638 AC: 2649 AN: 41490

American (AMR) AF: 0.174 AC: 2663 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.227 AC: 789 AN: 3470

East Asian (EAS) AF: 0.00174 AC: 9 AN: 5178

South Asian (SAS) AF: 0.0722 AC: 348 AN: 4820

European-Finnish (FIN) AF: 0.169 AC: 1785 AN: 10554

Middle Eastern (MID) AF: 0.184 AC: 54 AN: 294

European-Non Finnish (NFE) AF: 0.249 AC: 16928 AN: 67978

Other (OTH) AF: 0.209 AC: 440 AN: 2110

Alfa AF: 0.221 Hom.: 7526

Bravo AF: 0.169

Asia WGS AF: 0.0410 AC: 144 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	0.29
DANN	Benign	0.81
PhyloP100		-0.99
Mutation Taster		=100/0	polymorphism (auto)

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: rs10498658; hg19: chr6-3104696;