rs2838113

Positions:

• chr21-41741645-G-A

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_020639.3(RIPK4):​c.1548C>T​(p.Asp516Asp) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.611 in 1,613,212 control chromosomes in the GnomAD database, including 305,174 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.54 (23812 hom., cov: 34)
  • Exomes 𝑓: 0.62 (281362 hom.)
• Consequence: RIPK4 NM_020639.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.397

Genes affected

RIPK4 (HGNC:496): (receptor interacting serine/threonine kinase 4) The protein encoded by this gene is a serine/threonine protein kinase that interacts with protein kinase C-delta. The encoded protein can also activate NFkappaB and is required for keratinocyte differentiation. This kinase undergoes autophosphorylation. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.56).
• BP6: Variant 21-41741645-G-A is Benign according to our data. Variant chr21-41741645-G-A is described in ClinVar as [Benign]. Clinvar id is 261349.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.397 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.624 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RIPK4	NM_020639.3	c.1548C>T	p.Asp516Asp	synonymous_variant	8/8	ENST00000332512.8	NP_065690.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RIPK4	ENST00000332512.8	c.1548C>T	p.Asp516Asp	synonymous_variant	8/8	1	NM_020639.3	ENSP00000332454.3
RIPK4	ENST00000352483.3	c.1692C>T	p.Asp564Asp	synonymous_variant	9/9	5		ENSP00000330161.2

Frequencies

GnomAD3 genomes AF: 0.540 AC: 82148 AN: 152018 Hom.: 23819 Cov.: 34

Gnomad AFR AF: 0.307

Gnomad AMI AF: 0.688

Gnomad AMR AF: 0.621

Gnomad ASJ AF: 0.662

Gnomad EAS AF: 0.629

Gnomad SAS AF: 0.637

Gnomad FIN AF: 0.620

Gnomad MID AF: 0.649

Gnomad NFE AF: 0.629

Gnomad OTH AF: 0.581

GnomAD3 exomes AF: 0.608 AC: 152476 AN: 250904 Hom.: 47405 AF XY: 0.617 AC XY: 83770 AN XY: 135678

Gnomad AFR exome AF: 0.298

Gnomad AMR exome AF: 0.611

Gnomad ASJ exome AF: 0.648

Gnomad EAS exome AF: 0.618

Gnomad SAS exome AF: 0.637

Gnomad FIN exome AF: 0.623

Gnomad NFE exome AF: 0.633

Gnomad OTH exome AF: 0.635

GnomAD4 exome AF: 0.618 AC: 903029 AN: 1461076 Hom.: 281362 Cov.: 79 AF XY: 0.620 AC XY: 450825 AN XY: 726904

Gnomad4 AFR exome AF: 0.296

Gnomad4 AMR exome AF: 0.612

Gnomad4 ASJ exome AF: 0.648

Gnomad4 EAS exome AF: 0.632

Gnomad4 SAS exome AF: 0.640

Gnomad4 FIN exome AF: 0.615

Gnomad4 NFE exome AF: 0.626

Gnomad4 OTH exome AF: 0.604

GnomAD4 genome AF: 0.540 AC: 82156 AN: 152136 Hom.: 23812 Cov.: 34 AF XY: 0.543 AC XY: 40419 AN XY: 74372

Gnomad4 AFR AF: 0.306

Gnomad4 AMR AF: 0.622

Gnomad4 ASJ AF: 0.662

Gnomad4 EAS AF: 0.629

Gnomad4 SAS AF: 0.636

Gnomad4 FIN AF: 0.620

Gnomad4 NFE AF: 0.629

Gnomad4 OTH AF: 0.579

Alfa AF: 0.613 Hom.: 37092

Bravo AF: 0.533

Asia WGS AF: 0.588 AC: 2045 AN: 3478

EpiCase AF: 0.638

EpiControl AF: 0.638

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Bartsocas-Papas syndrome 1 Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Nov 07, 2021	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 05, 2019	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.56
CADD	Benign	6.7
DANN	Benign	0.86

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

LitVar

Other links and lift over

dbSNP: rs2838113; hg19: chr21-43161805; COSMIC: COSV60185708; COSMIC: COSV60185708;