rs864309489

chr6-83857300-CT-C

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP5_Moderate

The NM_001009994.3(RIPPLY2):c.299del(p.Leu100ArgfsTer25) variant causes a frameshift change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: RIPPLY2 NM_001009994.3 frameshift
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1 U:1
• Conservation: PhyloP100: 7.08

Genes affected

RIPPLY2 (HGNC:21390): (ripply transcriptional repressor 2) This gene encodes a nuclear protein that belongs to a novel family of proteins required for vertebrate somitogenesis. Members of this family have a tetrapeptide WRPW motif that is required for interaction with the transcriptional repressor Groucho and a carboxy-terminal Ripply homology domain/Bowline-DSCR-Ledgerline conserved region required for transcriptional repression. Null mutant mice die soon after birth and display defects in axial skeleton segmentation due to defective somitogenesis. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Feb 2016]

RIPPLY2-CYB5R4 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 6-83857300-CT-C is Pathogenic according to our data. Variant chr6-83857300-CT-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 218314.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RIPPLY2	NM_001009994.3	c.299del	p.Leu100ArgfsTer25	frameshift_variant	4/4	ENST00000369689.6
RIPPLY2-CYB5R4	NR_174604.1	n.296+3140del		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RIPPLY2	ENST00000369689.6	c.299del	p.Leu100ArgfsTer25	frameshift_variant	4/4	1	NM_001009994.3	P1
RIPPLY2	ENST00000369687.2	c.125del	p.Leu42ArgfsTer25	frameshift_variant	3/3	2
RIPPLY2	ENST00000635617.1	n.3712del		non_coding_transcript_exon_variant	1/1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 27

GnomAD4 genome Cov.: 33

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1 Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Klippel-Feil syndrome 2, autosomal recessive Pathogenic:1

Likely pathogenic, criteria provided, single submitter

research

Lupski Lab, Baylor-Hopkins CMG, Baylor College of Medicine

-

Our clinical and genomic findings, together with animal model data and clinical reports in the literature, suggest that a homozygous frameshift mutation is responsible for a new type of autosomal recessive KFS. Additional reports of individuals with a similar phenotype and animal studies will be crucial to clarify the potential role of RIPPLY2 in the etiology of heterotaxy. -

not provided Uncertain:1

Uncertain significance, no assertion criteria provided

literature only

OMIM

Nov 01, 2015

- -

Computational scores

Source: dbNSFP v4.3

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: rs864309489; hg19: chr6-84567019;