2-46618839-G-A

Variant names:

• chr2-46618839-G-A
• NM_014171.6:c.82+1G>A

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PVS1_Strong PM2 PP5_Moderate

The NM_014171.6(CRIPT):​c.82+1G>A variant causes a splice donor, intron change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000007 in 1,428,450 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.0e-7 (0 hom.)
• Consequence: CRIPT NM_014171.6 splice_donor, intron
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 8.87
• Publications: 0 publications found

Genes affected

CRIPT (HGNC:14312): (CXXC repeat containing interactor of PDZ3 domain) This gene encodes a protein that binds to the PDZ3 peptide recognition domain. The encoded protein may modulates protein interactions with the cytoskeleton. A mutation in this gene resulted in short stature with microcephaly and distinctive facies. [provided by RefSeq, Jun 2014]

CRIPT Gene-Disease associations (from GenCC):

• Rothmund-Thomson syndrome, type 3

  Inheritance: AR Classification: STRONG, MODERATE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, G2P

ACMG classification

Our verdict: Likely_pathogenic. The variant received 8 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.21568628 fraction of the gene. No cryptic splice site detected. Exon removal is inframe change.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 2-46618839-G-A is Pathogenic according to our data. Variant chr2-46618839-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1997112.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CRIPT	NM_014171.6	c.82+1G>A		splice_donor_variant, intron_variant	Intron 2 of 4	ENST00000238892.4	NP_054890.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CRIPT	ENST00000238892.4	c.82+1G>A		splice_donor_variant, intron_variant	Intron 2 of 4	1	NM_014171.6	ENSP00000238892.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 7.00e-7 AC: 1 AN: 1428450 Hom.: 0 Cov.: 24 AF XY: 0.00000140 AC XY: 1 AN XY: 711888

African (AFR) AF: 0.00 AC: 0 AN: 32264

American (AMR) AF: 0.00 AC: 0 AN: 41700

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25544

East Asian (EAS) AF: 0.00 AC: 0 AN: 39032

South Asian (SAS) AF: 0.00 AC: 0 AN: 83050

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53214

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5588

European-Non Finnish (NFE) AF: 9.18e-7 AC: 1 AN: 1088890

Other (OTH) AF: 0.00 AC: 0 AN: 59168

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Pathogenic:1

May 24, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. This variant has not been reported in the literature in individuals affected with CRIPT-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change affects a donor splice site in intron 2 of the CRIPT gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in CRIPT are known to be pathogenic (PMID: 24389050, 27250922). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.62	D
BayesDel_noAF	Pathogenic	0.42
CADD	Pathogenic	33
DANN	Uncertain	1.0
Eigen	Pathogenic	1.2
Eigen_PC	Pathogenic	1.1
FATHMM_MKL	Pathogenic	0.99	D
PhyloP100		8.9
GERP RS		5.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.9
Mutation Taster		=1/99	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.94
SpliceAI score (max)		1.0		Details are displayed if max score is > 0.2
DS_DL_spliceai		1.0		Position offset: -1

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

hg19: chr2-46845978;