Variant chr2-46618827-G-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4BS1_Supporting

The NM_014171.6(CRIPT):c.71G>A(p.Arg24Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000622 in 1,447,610 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 Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000062 ( 0 hom. )

Consequence

CRIPT
NM_014171.6 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 8.87

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.29092592).

BS1

Variant frequency is greater than expected in population amr. gnomad4_exome allele frequency = 0.00000622 (9/1447610) while in subpopulation AMR AF= 0.000138 (6/43454). AF 95% confidence interval is 0.0000594. There are 0 homozygotes in gnomad4_exome. There are 4 alleles in male gnomad4_exome subpopulation. Median coverage is 26. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CRIPT	NM_014171.6 linkuse as main transcript	c.71G>A	p.Arg24Lys	missense_variant	2/5	ENST00000238892.4	NP_054890.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CRIPT	ENST00000238892.4 linkuse as main transcript	c.71G>A	p.Arg24Lys	missense_variant	2/5	1	NM_014171.6	ENSP00000238892	P1
CRIPT	ENST00000486447.1 linkuse as main transcript	n.663G>A		non_coding_transcript_exon_variant	2/5	5

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.0000325

AC:

AN:

246064

Hom.:

AF XY:

0.0000150

AC XY:

AN XY:

133226

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000183

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000340

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000890

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000622

AC:

AN:

1447610

Hom.:

Cov.:

AF XY:

0.00000555

AC XY:

AN XY:

720802

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000138

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000354

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ExAC

AF:

0.0000494

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

May 26, 2022

This sequence change replaces arginine, which is basic and polar, with lysine, which is basic and polar, at codon 24 of the CRIPT protein (p.Arg24Lys). This variant is present in population databases (rs753774289, gnomAD 0.02%). This variant has not been reported in the literature in individuals affected with CRIPT-related conditions. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.38

BayesDel_addAF

Benign

-0.12

BayesDel_noAF

Benign

-0.14

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.25

Eigen

Uncertain

0.32

Eigen_PC

Uncertain

0.46

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.93

M_CAP

Benign

0.0059

MetaRNN

Benign

0.29

MetaSVM

Benign

-0.61

MutationAssessor

Uncertain

2.6

MutationTaster

Benign

1.0

PrimateAI

Pathogenic

0.82

PROVEAN

Benign

-1.6

REVEL

Benign

0.17

Sift

Benign

0.27

Sift4G

Benign

0.30

Polyphen

0.12

Vest4

0.52

MutPred

0.69

Gain of ubiquitination at R24 (P = 0.009);

MVP

0.64

MPC

0.017

ClinPred

0.22

GERP RS

5.5

RBP_binding_hub_radar

0.92

RBP_regulation_power_radar

2.6

Varity_R

0.34

gMVP

0.33

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over