NM_001009994.3:c.75G>T

Variant names:

• chr6-83853491-G-T
• rs1426596059
• NM_001009994.3:c.75G>T

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 2P and 7B. PM2 BP4_Strong BP6_Moderate BP7

The NM_001009994.3(RIPPLY2):​c.75G>T​(p.Arg25Arg) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000721 in 1,386,476 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 7.2e-7 (0 hom.)
• Consequence: RIPPLY2 NM_001009994.3 synonymous
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.383
• 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 -5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.79).
• BP6: Variant 6-83853491-G-T is Benign according to our data. Variant chr6-83853491-G-T is described in ClinVar as Likely_benign. ClinVar VariationId is 1567635.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=-0.383 with no splicing effect.

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.75G>T	p.Arg25Arg	synonymous	Exon 1 of 4	NP_001009994.1	Q5TAB7-1
	RIPPLY2	NM_001400900.1		c.75G>T	p.Arg25Arg	synonymous	Exon 1 of 3	NP_001387829.1
	RIPPLY2-CYB5R4	NR_174604.1		n.132G>T		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.75G>T	p.Arg25Arg	synonymous	Exon 1 of 4	ENSP00000358703.1	Q5TAB7-1
	ENSG00000287705	ENST00000656981.1		n.677C>A		non_coding_transcript_exon	Exon 1 of 1
	RIPPLY2	ENST00000369687.2	TSL:2	c.-283G>T		upstream_gene	N/A	ENSP00000358701.1	Q5TAB7-2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 7.21e-7 AC: 1 AN: 1386476 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 683922

African (AFR) AF: 0.00 AC: 0 AN: 31244

American (AMR) AF: 0.00 AC: 0 AN: 34554

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24958

East Asian (EAS) AF: 0.00 AC: 0 AN: 35644

South Asian (SAS) AF: 0.00 AC: 0 AN: 78904

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 41968

Middle Eastern (MID) AF: 0.000236 AC: 1 AN: 4232

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1077398

Other (OTH) AF: 0.00 AC: 0 AN: 57574

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	6.2
DANN	Benign	0.76
PhyloP100		-0.38
PromoterAI		-0.0010	Neutral

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: rs1426596059; hg19: chr6-84563210;