22-49918866-C-T

Variant names:

• chr22-49918866-C-T
• rs1272735690
• NM_024324.5:c.97C>T

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_024324.5(CRELD2):​c.97C>T​(p.Arg33Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000536 in 1,305,994 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. R33G) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0000052 (0 hom.)
• Consequence: CRELD2 NM_024324.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.120
• 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: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.33437675).

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.97C>T	p.Arg33Trp	missense	Exon 1 of 10	NP_077300.3
	CRELD2	NM_001135101.3		c.97C>T	p.Arg33Trp	missense	Exon 1 of 11	NP_001128573.1	Q6UXH1-5
	CRELD2	NM_001284317.2		c.97C>T	p.Arg33Trp	missense	Exon 1 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.97C>T	p.Arg33Trp	missense	Exon 1 of 10	ENSP00000332223.4	Q6UXH1-1
	CRELD2	ENST00000404488.7	TSL:1	c.97C>T	p.Arg33Trp	missense	Exon 1 of 11	ENSP00000383938.3	Q6UXH1-5
	CRELD2	ENST00000403427.3	TSL:1	c.97C>T	p.Arg33Trp	missense	Exon 1 of 9	ENSP00000384111.3	Q6UXH1-4

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152176 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00 AC: 0 AN: 1702 AF XY: 0.00

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: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000520 AC: 6 AN: 1153818 Hom.: 0 Cov.: 31 AF XY: 0.00000540 AC XY: 3 AN XY: 555360

African (AFR) AF: 0.00 AC: 0 AN: 23306

American (AMR) AF: 0.00 AC: 0 AN: 9226

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 15660

East Asian (EAS) AF: 0.00 AC: 0 AN: 27008

South Asian (SAS) AF: 0.0000238 AC: 1 AN: 42056

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 25290

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3178

European-Non Finnish (NFE) AF: 0.00000520 AC: 5 AN: 961482

Other (OTH) AF: 0.00 AC: 0 AN: 46612

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152176 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 74352

African (AFR) AF: 0.00 AC: 0 AN: 41468

American (AMR) AF: 0.00 AC: 0 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10616

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68018

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

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	0.12
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Benign	-0.42
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.026	T
Eigen	Benign	-0.33
Eigen_PC	Benign	-0.56
FATHMM_MKL	Benign	0.0033	N
LIST_S2	Uncertain	0.93	D
M_CAP	Pathogenic	0.29	D
MetaRNN	Benign	0.33	T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	1.6	L
PhyloP100		-0.12
PrimateAI	Uncertain	0.64	T
PROVEAN	Uncertain	-3.0	D
REVEL	Benign	0.084
Sift	Benign	0.032	D
Sift4G	Uncertain	0.013	D
Polyphen		1.0	D
Vest4		0.32
MutPred		0.51		Loss of disorder (P = 0.0041)
MVP		0.63
MPC		0.66
ClinPred		0.96	D
GERP RS		-0.21
PromoterAI		-0.0080	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.069
gMVP		0.67
Mutation Taster		=98/2	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs1272735690; hg19: chr22-50312514;