chr2-46619669-CA-C

Position:

• chr2-46619669-CA-C

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_014171.6(CRIPT):​c.132del​(p.Ala45GlnfsTer86) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000549 in 1,458,184 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000055 (0 hom.)
• Consequence: CRIPT NM_014171.6 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 1.06

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]

ACMG classification

Verdict is Pathogenic. Variant got 18 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 2-46619669-CA-C is Pathogenic according to our data. Variant chr2-46619669-CA-C is described in ClinVar as [Pathogenic]. Clinvar id is 976761.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-46619669-CA-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CRIPT	NM_014171.6	c.132del	p.Ala45GlnfsTer86	frameshift_variant	3/5	ENST00000238892.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CRIPT	ENST00000238892.4	c.132del	p.Ala45GlnfsTer86	frameshift_variant	3/5	1	NM_014171.6	P1
CRIPT	ENST00000486447.1	n.724del		non_coding_transcript_exon_variant	3/5	5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000549 AC: 8 AN: 1458184 Hom.: 0 Cov.: 29 AF XY: 0.00000689 AC XY: 5 AN XY: 725438

Gnomad4 AFR exome AF: 0.0000301

Gnomad4 AMR exome AF: 0.0000452

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000254

Gnomad4 SAS exome AF: 0.0000117

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Rothmund-Thomson syndrome, type 3 Pathogenic:3

Pathogenic, no assertion criteria provided	literature only	OMIM	Apr 29, 2024	- -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München	Feb 19, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	MGZ Medical Genetics Center	Dec 14, 2021	- -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs771238795; hg19: chr2-46846808;