8-89769900-A-T

Variant names:

• chr8-89769900-A-T
• rs56257721
• NM_003821.6:c.612A>T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_003821.6(RIPK2):​c.612A>T​(p.Ser204Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00194 in 1,607,632 control chromosomes in the GnomAD database, including 45 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.010 (32 hom., cov: 32)
  • Exomes 𝑓: 0.0011 (13 hom.)
• Consequence: RIPK2 NM_003821.6 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.99

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: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.78).
• BP6: Variant 8-89769900-A-T is Benign according to our data. Variant chr8-89769900-A-T is described in ClinVar as [Benign]. Clinvar id is 707947.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.99 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.01 (1521/151958) while in subpopulation AFR AF = 0.0343 (1424/41510). AF 95% confidence interval is 0.0328. There are 32 homozygotes in GnomAd4. There are 677 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position FAILED quality control check.
• BS2: High AC in GnomAd4 at 1521 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RIPK2	NM_003821.6	c.612A>T	p.Ser204Ser	synonymous_variant	Exon 4 of 11	ENST00000220751.5	NP_003812.1
RIPK2	NM_001375360.1	c.201A>T	p.Ser67Ser	synonymous_variant	Exon 3 of 10		NP_001362289.1
RIPK2	XM_011517357.3	c.99A>T	p.Ser33Ser	synonymous_variant	Exon 2 of 9		XP_011515659.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RIPK2	ENST00000220751.5	c.612A>T	p.Ser204Ser	synonymous_variant	Exon 4 of 11	1	NM_003821.6	ENSP00000220751.4
RIPK2	ENST00000522965.1	n.*251A>T		non_coding_transcript_exon_variant	Exon 3 of 10	1		ENSP00000429271.1
RIPK2	ENST00000522965.1	n.*251A>T		3_prime_UTR_variant	Exon 3 of 10	1		ENSP00000429271.1

Frequencies

GnomAD3 genomes AF: 0.0100 AC: 1520 AN: 151840 Hom.: 32 Cov.: 32

Gnomad AFR AF: 0.0344

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00500

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000147

Gnomad OTH AF: 0.00479

GnomAD2 exomes AF: 0.00260 AC: 642 AN: 246756 AF XY: 0.00192

Gnomad AFR exome AF: 0.0329

Gnomad AMR exome AF: 0.00263

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000197

Gnomad OTH exome AF: 0.00150

GnomAD4 exome AF: 0.00110 AC: 1595 AN: 1455674 Hom.: 13 Cov.: 31 AF XY: 0.000958 AC XY: 694 AN XY: 724156

Gnomad4 AFR exome AF: 0.0337 AC: 1113 AN: 32986

Gnomad4 AMR exome AF: 0.00278 AC: 122 AN: 43896

Gnomad4 ASJ exome AF: 0.00 AC: 0 AN: 25966

Gnomad4 EAS exome AF: 0.00 AC: 0 AN: 39272

Gnomad4 SAS exome AF: 0.0000585 AC: 5 AN: 85500

Gnomad4 FIN exome AF: 0.00 AC: 0 AN: 53336

Gnomad4 NFE exome AF: 0.000210 AC: 233 AN: 1108846

Gnomad4 Remaining exome AF: 0.00193 AC: 116 AN: 60130

GnomAD4 genome AF: 0.0100 AC: 1521 AN: 151958 Hom.: 32 Cov.: 32 AF XY: 0.00911 AC XY: 677 AN XY: 74306

Gnomad4 AFR AF: 0.0343 AC: 0.034305 AN: 0.034305

Gnomad4 AMR AF: 0.00500 AC: 0.00499671 AN: 0.00499671

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: 0.000147 AC: 0.000147414 AN: 0.000147414

Gnomad4 OTH AF: 0.00474 AC: 0.00474383 AN: 0.00474383

Alfa AF: 0.00347 Hom.: 5

Bravo AF: 0.0114

Asia WGS AF: 0.000867 AC: 4 AN: 3476

EpiCase AF: 0.000110

EpiControl AF: 0.000361

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

May 31, 2018

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.78
CADD	Benign	5.9
DANN	Benign	0.67
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs56257721; hg19: chr8-90782128;