2-36356616-T-C

Variant names:

• chr2-36356616-T-C
• rs140753944
• NM_016441.3:c.324T>C

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 0P and 7B. BP6_Moderate BP7 BS2

The NM_016441.3(CRIM1):​c.324T>C​(p.Val108Val) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000657 in 1,606,594 control chromosomes in the GnomAD database, including 7 homozygotes. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0026 (3 hom., cov: 32)
  • Exomes 𝑓: 0.00046 (4 hom.)
• Consequence: CRIM1 NM_016441.3 synonymous
• Clinical Significance: Benign criteria provided, single submitter B:2
• Conservation: PhyloP100: 0.418
• Publications: 0 publications found

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)

ACMG classification

Our verdict: Benign. The variant received -7 ACMG points.

• BP6: Variant 2-36356616-T-C is Benign according to our data. Variant chr2-36356616-T-C is described in ClinVar as [Benign]. Clinvar id is 708457.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=0.418 with no splicing effect.
• BS2: High AC in GnomAd4 at 388 AD,Unknown gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CRIM1	NM_016441.3	c.324T>C	p.Val108Val	synonymous_variant	Exon 1 of 17	ENST00000280527.7	NP_057525.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CRIM1	ENST00000280527.7	c.324T>C	p.Val108Val	synonymous_variant	Exon 1 of 17	1	NM_016441.3	ENSP00000280527.2
CRIM1	ENST00000426856.1	c.174T>C	p.Val58Val	synonymous_variant	Exon 1 of 4	3		ENSP00000407636.1
CRIM1	ENST00000428774.1	c.144T>C	p.Val48Val	synonymous_variant	Exon 1 of 2	3		ENSP00000415706.1

Frequencies

GnomAD3 genomes AF: 0.00257 AC: 389 AN: 151616 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.00847

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000982

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000391

Gnomad SAS AF: 0.00438

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.000957

GnomAD2 exomes AF: 0.00131 AC: 315 AN: 240974 AF XY: 0.00123

Gnomad AFR exome AF: 0.0109

Gnomad AMR exome AF: 0.000647

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000443

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000920

Gnomad OTH exome AF: 0.000680

GnomAD4 exome AF: 0.000458 AC: 667 AN: 1454860 Hom.: 4 Cov.: 31 AF XY: 0.000506 AC XY: 366 AN XY: 723552

African (AFR) AF: 0.00833 AC: 278 AN: 33362

American (AMR) AF: 0.000742 AC: 33 AN: 44488

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25982

East Asian (EAS) AF: 0.000304 AC: 12 AN: 39530

South Asian (SAS) AF: 0.00327 AC: 281 AN: 85900

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49968

Middle Eastern (MID) AF: 0.000347 AC: 2 AN: 5760

European-Non Finnish (NFE) AF: 0.00000360 AC: 4 AN: 1109698

Other (OTH) AF: 0.000947 AC: 57 AN: 60172

GnomAD4 genome AF: 0.00256 AC: 388 AN: 151734 Hom.: 3 Cov.: 32 AF XY: 0.00226 AC XY: 168 AN XY: 74194

African (AFR) AF: 0.00844 AC: 349 AN: 41334

American (AMR) AF: 0.000981 AC: 15 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3464

East Asian (EAS) AF: 0.000392 AC: 2 AN: 5104

South Asian (SAS) AF: 0.00418 AC: 20 AN: 4786

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10574

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 286

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67876

Other (OTH) AF: 0.000947 AC: 2 AN: 2112

Alfa AF: 0.00166 Hom.: 0

Bravo AF: 0.00317

Asia WGS AF: 0.00260 AC: 9 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Dec 31, 2019

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

CRIM1-related disorder Benign:1

Oct 28, 2019

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.72
CADD	Benign	12
DANN	Benign	0.74
PhyloP100		0.42
PromoterAI		-0.058	Neutral
Mutation Taster		=100/0	polymorphism

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

Other links and lift over

dbSNP: rs140753944; hg19: chr2-36583759;