2-36356596-A-C

Position:

• chr2-36356596-A-C

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_016441.3(CRIM1):​c.304A>C​(p.Thr102Pro) variant causes a missense change. The variant allele was found at a frequency of 0.000000686 in 1,458,638 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: 6.9e-7 (0 hom.)
• Consequence: CRIM1 NM_016441.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.82

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.4056587).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CRIM1	NM_016441.3	c.304A>C	p.Thr102Pro	missense_variant	1/17	ENST00000280527.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CRIM1	ENST00000280527.7	c.304A>C	p.Thr102Pro	missense_variant	1/17	1	NM_016441.3	P1
CRIM1	ENST00000426856.1	c.154A>C	p.Thr52Pro	missense_variant	1/4	3
CRIM1	ENST00000428774.1	c.127A>C	p.Thr43Pro	missense_variant	1/2	3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.86e-7 AC: 1 AN: 1458638 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 725716

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: 9.00e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 12, 2024

The c.304A>C (p.T102P) alteration is located in exon 1 (coding exon 1) of the CRIM1 gene. This alteration results from a A to C substitution at nucleotide position 304, causing the threonine (T) at amino acid position 102 to be replaced by a proline (P). 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	Benign	0.19
BayesDel_addAF	Uncertain	0.019	T
BayesDel_noAF	Benign	-0.21
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Benign	0.047	T;.
Eigen	Benign	-0.023
Eigen_PC	Benign	0.011
FATHMM_MKL	Benign	0.66	D
LIST_S2	Benign	0.72	T;T
M_CAP	Pathogenic	0.79	D
MetaRNN	Benign	0.41	T;T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	0.26	N;.
MutationTaster	Benign	1.0	D
PrimateAI	Pathogenic	0.90	D
PROVEAN	Benign	-0.090	N;N
REVEL	Benign	0.25
Sift	Benign	0.15	T;T
Sift4G	Uncertain	0.014	D;T
Polyphen		0.74	P;.
Vest4		0.39
MutPred		0.30		Gain of disorder (P = 0.0713);.;
MVP		0.46
MPC		0.36
ClinPred		0.71	D
GERP RS		2.3
Varity_R		0.12
gMVP		0.56

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

Other links and lift over

dbSNP: rs753441532; hg19: chr2-36583739;