chr6-83853425-C-G

Variant names:

• chr6-83853425-C-G
• rs758151366
• NM_001009994.3:c.9C>G

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001009994.3(RIPPLY2):​c.9C>G​(p.Asn3Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. N3N) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 33)
• Consequence: RIPPLY2 NM_001009994.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.868
• Publications: 0 publications found

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 Gene-Disease associations (from GenCC):

• spondylocostal dysostosis 6, autosomal recessive

  Inheritance: AR, Unknown Classification: STRONG, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics
• autosomal recessive spondylocostal dysostosis

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ENSG00000287705 (HGNC:):

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.047851086).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001009994.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RIPPLY2	NM_001009994.3	MANE Select	c.9C>G	p.Asn3Lys	missense	Exon 1 of 4	NP_001009994.1	Q5TAB7-1
	RIPPLY2	NM_001400900.1		c.9C>G	p.Asn3Lys	missense	Exon 1 of 3	NP_001387829.1
	RIPPLY2-CYB5R4	NR_174604.1		n.66C>G		non_coding_transcript_exon	Exon 1 of 18

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RIPPLY2	ENST00000369689.6	TSL:1 MANE Select	c.9C>G	p.Asn3Lys	missense	Exon 1 of 4	ENSP00000358703.1	Q5TAB7-1
	ENSG00000287705	ENST00000656981.1		n.743G>C		non_coding_transcript_exon	Exon 1 of 1
	RIPPLY2	ENST00000369687.2	TSL:2	c.-349C>G		upstream_gene	N/A	ENSP00000358701.1	Q5TAB7-2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.32	T
BayesDel_noAF	Benign	-0.69
CADD	Benign	1.8
DANN	Benign	0.89
DEOGEN2	Benign	0.11	T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.080	N
LIST_S2	Benign	0.28	T
M_CAP	Benign	0.0089	T
MetaRNN	Benign	0.048	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.0	N
PhyloP100		-0.87
PrimateAI	Uncertain	0.72	T
PROVEAN	Benign	-0.020	N
REVEL	Benign	0.016
Sift	Benign	0.030	D
Sift4G	Benign	0.15	T
Polyphen		0.0020	B
Vest4		0.064
MutPred		0.17		Gain of ubiquitination at N3 (P = 0.0039)
MVP		0.18
MPC		0.10
ClinPred		0.11	T
GERP RS		-0.59
PromoterAI		0.087	Neutral
Varity_R		0.045
gMVP		0.065
Mutation Taster		=98/2	polymorphism

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: rs758151366; hg19: chr6-84563144;