Genetic Variant CRIM1:p.Glu72Gly (chr2-36356507-A-G) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_016441.3(CRIM1):c.215A>G(p.Glu72Gly) variant causes a missense change. The variant allele was found at a frequency of 0.00000274 in 1,460,714 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000027 ( 0 hom. )

Consequence

CRIM1
NM_016441.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 5.37

Publications

1 publications found

Variant links:

Genes affected

CRIM1 (HGNC:2359): (cysteine rich transmembrane BMP regulator 1) This gene encodes a transmembrane protein containing six cysteine-rich repeat domains and an insulin-like growth factor-binding domain. The encoded protein may play a role in tissue development though interactions with members of the transforming growth factor beta family, such as bone morphogenetic proteins. [provided by RefSeq, Nov 2010]

CRIM1 Gene-Disease associations (from GenCC):

colobomatous macrophthalmia-microcornea syndrome
Inheritance: AD, Unknown Classification: SUPPORTIVE, LIMITED Submitted by: Orphanet, Labcorp Genetics (formerly Invitae)

CRIM1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CRIM1	NM_016441.3 link	c.215A>G	p.Glu72Gly	missense_variant	Exon 1 of 17	ENST00000280527.7	NP_057525.1	Q9NZV1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
CRIM1	ENST00000280527.7 link	c.215A>G	p.Glu72Gly	missense_variant	Exon 1 of 17	1	NM_016441.3	ENSP00000280527.2	Q9NZV1
CRIM1	ENST00000426856.1 link	c.65A>G	p.Glu22Gly	missense_variant	Exon 1 of 4	3		ENSP00000407636.1	H7C2T6
CRIM1	ENST00000428774.1 link	c.35A>G	p.Glu12Gly	missense_variant	Exon 1 of 2	3		ENSP00000415706.1	H7C458

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000403

AC:

AN:

248182

AF XY:

0.00000741

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000898

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000274

AC:

AN:

1460714

Hom.:

Cov.:

AF XY:

0.00000275

AC XY:

AN XY:

726706

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33470

American (AMR)

AF:

0.00

AC:

AN:

44716

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26112

East Asian (EAS)

AF:

0.00

AC:

AN:

39690

South Asian (SAS)

AF:

0.00

AC:

AN:

86254

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52484

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.00000270

AC:

AN:

1111856

Other (OTH)

AF:

0.0000166

AC:

AN:

60366

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.438

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

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

Feb 08, 2025

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.215A>G (p.E72G) alteration is located in exon 1 (coding exon 1) of the CRIM1 gene. This alteration results from a A to G substitution at nucleotide position 215, causing the glutamic acid (E) at amino acid position 72 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

0.58

BayesDel_addAF

Uncertain

0.077

BayesDel_noAF

Benign

-0.13

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.18

T;.

Eigen

Uncertain

0.33

Eigen_PC

Uncertain

0.30

FATHMM_MKL

Uncertain

0.88

LIST_S2

Benign

0.84

T;T

M_CAP

Pathogenic

0.93

MetaRNN

Uncertain

0.65

D;D

MetaSVM

Benign

-0.33

MutationAssessor

Pathogenic

3.3

M;.

PhyloP100

5.4

PrimateAI

Pathogenic

0.84

PROVEAN

Benign

-1.7

N;D

REVEL

Pathogenic

0.66

Sift

Uncertain

0.0050

D;D

Sift4G

Uncertain

0.0080

D;T

Polyphen

1.0

D;.

Vest4

0.70

MutPred

0.61

Gain of glycosylation at S73 (P = 0.0883);.;

MVP

0.56

MPC

0.77

ClinPred

0.93

GERP RS

3.3

PromoterAI

-0.045

Neutral

(source)

Varity_R

0.34

gMVP

0.86

Mutation Taster

=30/70

disease causing

(source)

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

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2-36356507-A-G

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over