6-83853366-T-C

Variant names:

• chr6-83853366-T-C
• rs9344362
• NM_001009994.3:c.-51T>C

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_001009994.3(RIPPLY2):​c.-51T>C variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0734 in 1,486,130 control chromosomes in the GnomAD database, including 12,880 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.18 (5252 hom., cov: 33)
  • Exomes 𝑓: 0.061 (7628 hom.)
• Consequence: RIPPLY2 NM_001009994.3 5_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.230
• Publications: 8 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: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP6: Variant 6-83853366-T-C is Benign according to our data. Variant chr6-83853366-T-C is described in ClinVar as Benign. ClinVar VariationId is 1247080.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.454 is higher than 0.05.

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.-51T>C		5_prime_UTR	Exon 1 of 4	NP_001009994.1	Q5TAB7-1
	RIPPLY2	NM_001400900.1		c.-51T>C		5_prime_UTR	Exon 1 of 3	NP_001387829.1
	RIPPLY2-CYB5R4	NR_174604.1		n.7T>C		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.-51T>C		5_prime_UTR	Exon 1 of 4	ENSP00000358703.1	Q5TAB7-1
	ENSG00000287705	ENST00000656981.1		n.802A>G		non_coding_transcript_exon	Exon 1 of 1
	RIPPLY2	ENST00000369687.2	TSL:2	c.-408T>C		upstream_gene	N/A	ENSP00000358701.1	Q5TAB7-2

Frequencies

GnomAD3 genomes AF: 0.182 AC: 27741 AN: 152114 Hom.: 5229 Cov.: 33

Gnomad AFR AF: 0.459

Gnomad AMI AF: 0.0351

Gnomad AMR AF: 0.246

Gnomad ASJ AF: 0.0170

Gnomad EAS AF: 0.267

Gnomad SAS AF: 0.0572

Gnomad FIN AF: 0.0525

Gnomad MID AF: 0.0570

Gnomad NFE AF: 0.0346

Gnomad OTH AF: 0.139

GnomAD2 exomes AF: 0.131 AC: 16595 AN: 126248 AF XY: 0.115

Gnomad AFR exome AF: 0.481

Gnomad AMR exome AF: 0.329

Gnomad ASJ exome AF: 0.0169

Gnomad EAS exome AF: 0.272

Gnomad FIN exome AF: 0.0534

Gnomad NFE exome AF: 0.0344

Gnomad OTH exome AF: 0.0855

GnomAD4 exome AF: 0.0609 AC: 81287 AN: 1333898 Hom.: 7628 Cov.: 22 AF XY: 0.0588 AC XY: 38822 AN XY: 660470

African (AFR) AF: 0.480 AC: 14186 AN: 29564

American (AMR) AF: 0.310 AC: 10435 AN: 33658

Ashkenazi Jewish (ASJ) AF: 0.0150 AC: 365 AN: 24290

East Asian (EAS) AF: 0.239 AC: 8419 AN: 35278

South Asian (SAS) AF: 0.0543 AC: 4187 AN: 77150

European-Finnish (FIN) AF: 0.0562 AC: 2146 AN: 38176

Middle Eastern (MID) AF: 0.0605 AC: 276 AN: 4562

European-Non Finnish (NFE) AF: 0.0353 AC: 36511 AN: 1035394

Other (OTH) AF: 0.0853 AC: 4762 AN: 55826

GnomAD4 genome AF: 0.183 AC: 27827 AN: 152232 Hom.: 5252 Cov.: 33 AF XY: 0.182 AC XY: 13581 AN XY: 74436

African (AFR) AF: 0.459 AC: 19083 AN: 41540

American (AMR) AF: 0.246 AC: 3767 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.0170 AC: 59 AN: 3470

East Asian (EAS) AF: 0.267 AC: 1376 AN: 5160

South Asian (SAS) AF: 0.0574 AC: 277 AN: 4824

European-Finnish (FIN) AF: 0.0525 AC: 557 AN: 10610

Middle Eastern (MID) AF: 0.0544 AC: 16 AN: 294

European-Non Finnish (NFE) AF: 0.0346 AC: 2355 AN: 68010

Other (OTH) AF: 0.144 AC: 305 AN: 2112

Alfa AF: 0.0896 Hom.: 811

Bravo AF: 0.214

Asia WGS AF: 0.168 AC: 584 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: 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	-0.84
CADD	Benign	7.2
DANN	Benign	0.60
PhyloP100		-0.23
PromoterAI		0.043	Neutral
Mutation Taster		=300/0	polymorphism (auto)

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: rs9344362; hg19: chr6-84563085; COSMIC: COSV63762507; COSMIC: COSV63762507;