Genetic Variant CRIP1:p.Arg68Gly (chr14-105488479-C-G) – ACMG Classification: Uncertain_significance (3 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 4P and 1B. PM1PM2BP4

The NM_001311.5(CRIP1):c.202C>G(p.Arg68Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000243 in 1,236,016 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 (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R68P) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000024 ( 0 hom. )

Consequence

CRIP1
NM_001311.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.386

Variant links:

Genes affected

CRIP1 (HGNC:2360): (cysteine rich protein 1) Cysteine-rich intestinal protein (CRIP) belongs to the LIM/double zinc finger protein family, members of which include cysteine- and glycine-rich protein-1 (CSRP1; MIM 123876), rhombotin-1 (RBTN1; MIM 186921), rhombotin-2 (RBTN2; MIM 180385), and rhombotin-3 (RBTN3; MIM 180386). CRIP may be involved in intestinal zinc transport (Hempe and Cousins, 1991 [PubMed 1946385]).[supplied by OMIM, Mar 2008]

CRIP1 links:

ENSG00000257341 (HGNC:):

ENSG00000257341 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 3 ACMG points.

PM1

In a modified_residue Omega-N-methylarginine (size 0) in uniprot entity CRIP1_HUMAN

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.293563).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CRIP1	NM_001311.5 link	c.202C>G	p.Arg68Gly	missense_variant	Exon 5 of 6	ENST00000392531.4	NP_001302.1	P50238

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CRIP1	ENST00000392531.4 link	c.202C>G	p.Arg68Gly	missense_variant	Exon 5 of 6	2	NM_001311.5	ENSP00000376315.3		P50238
ENSG00000257341	ENST00000477724.6 link	n.202C>G		non_coding_transcript_exon_variant	Exon 4 of 7	4		ENSP00000455329.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000243

AC:

AN:

1236016

Hom.:

Cov.:

AF XY:

0.00000327

AC XY:

AN XY:

612330

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000310

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Jun 16, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.202C>G (p.R68G) alteration is located in exon 5 (coding exon 4) of the CRIP1 gene. This alteration results from a C to G substitution at nucleotide position 202, causing the arginine (R) at amino acid position 68 to be replaced by a glycine (G). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.66

BayesDel_addAF

Uncertain

0.13

BayesDel_noAF

Uncertain

-0.050

CADD

Uncertain

DANN

Uncertain

0.97

DEOGEN2

Benign

0.13

T;T;T

Eigen

Benign

-0.23

Eigen_PC

Benign

-0.15

FATHMM_MKL

Benign

0.75

M_CAP

Pathogenic

0.54

MetaRNN

Benign

0.29

T;T;T

MetaSVM

Uncertain

-0.058

PrimateAI

Uncertain

0.54

PROVEAN

Uncertain

-2.6

D;D;D

REVEL

Uncertain

0.54

Sift

Benign

0.33

T;T;T

Sift4G

Benign

0.30

T;T;T

Polyphen

0.50

P;P;P

Vest4

0.45

MutPred

0.40

Loss of methylation at R68 (P = 0.0033);Loss of methylation at R68 (P = 0.0033);Loss of methylation at R68 (P = 0.0033);

MVP

0.81

MPC

0.082

ClinPred

0.76

GERP RS

2.7

Varity_R

0.25

gMVP

0.42

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

No publications associated with this variant yet.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over