22-49919792-A-G

Variant names:

• chr22-49919792-A-G
• NM_024324.5:c.275A>G

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_024324.5(CRELD2):​c.275A>G​(p.Gln92Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict 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. Q92H) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: CRELD2 NM_024324.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.84
• Publications: 0 publications found

Genes affected

CRELD2 (HGNC:28150): (cysteine rich with EGF like domains 2) Predicted to enable calcium ion binding activity and protein disulfide isomerase activity. Predicted to be located in Golgi apparatus; endoplasmic reticulum; and extracellular space. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.039679885).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_024324.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CRELD2	NM_024324.5	MANE Select	c.275A>G	p.Gln92Arg	missense	Exon 3 of 10	NP_077300.3
	CRELD2	NM_001135101.3		c.275A>G	p.Gln92Arg	missense	Exon 3 of 11	NP_001128573.1	Q6UXH1-5
	CRELD2	NM_001284317.2		c.275A>G	p.Gln92Arg	missense	Exon 3 of 9	NP_001271246.1	Q6UXH1-4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CRELD2	ENST00000328268.9	TSL:1 MANE Select	c.275A>G	p.Gln92Arg	missense	Exon 3 of 10	ENSP00000332223.4	Q6UXH1-1
	CRELD2	ENST00000404488.7	TSL:1	c.275A>G	p.Gln92Arg	missense	Exon 3 of 11	ENSP00000383938.3	Q6UXH1-5
	CRELD2	ENST00000403427.3	TSL:1	c.275A>G	p.Gln92Arg	missense	Exon 3 of 9	ENSP00000384111.3	Q6UXH1-4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.067
BayesDel_addAF	Benign	-0.23	T
BayesDel_noAF	Benign	-0.57
CADD	Benign	12
DANN	Benign	0.71
DEOGEN2	Benign	0.012	T
Eigen	Benign	-1.0
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.51	D
LIST_S2	Benign	0.64	T
M_CAP	Benign	0.0060	T
MetaRNN	Benign	0.040	T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	0.81	L
PhyloP100		1.8
PrimateAI	Benign	0.27	T
PROVEAN	Benign	-0.88	N
REVEL	Benign	0.041
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.020	B
Vest4		0.063
MutPred		0.46		Loss of solvent accessibility (P = 0.0468)
MVP		0.31
MPC		0.19
ClinPred		0.033	T
GERP RS		-0.84
Varity_R		0.046
gMVP		0.63
Mutation Taster		=96/4	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

hg19: chr22-50313440;