12-3627497-A-G
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Variant summary
Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP3_Moderate
The NM_001144958.2(CRACR2A):āc.1871T>Cā(p.Met624Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000232 in 1,551,800 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (ā ).
Frequency
Genomes: š 0.000020 ( 0 hom., cov: 32)
Exomes š: 0.000024 ( 0 hom. )
Consequence
CRACR2A
NM_001144958.2 missense
NM_001144958.2 missense
Scores
2
11
4
Clinical Significance
Conservation
PhyloP100: 8.58
Genes affected
CRACR2A (HGNC:28657): (calcium release activated channel regulator 2A) Enables GTPase activity and calcium ion binding activity. Involved in several processes, including activation of store-operated calcium channel activity; positive regulation of JNK cascade; and store-operated calcium entry. Located in several cellular components, including Golgi apparatus; Weibel-Palade body; and immunological synapse. [provided by Alliance of Genome Resources, Apr 2022]
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ACMG classification
Classification made for transcript
Verdict is Uncertain_significance. Variant got 4 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.911
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CRACR2A | NM_001144958.2 | c.1871T>C | p.Met624Thr | missense_variant | 17/20 | ENST00000440314.7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CRACR2A | ENST00000440314.7 | c.1871T>C | p.Met624Thr | missense_variant | 17/20 | 2 | NM_001144958.2 | P1 | |
CRACR2A | ENST00000333750.9 | c.*868T>C | 3_prime_UTR_variant, NMD_transcript_variant | 11/15 | 2 |
Frequencies
GnomAD3 genomes AF: 0.0000197 AC: 3AN: 152212Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000317 AC: 5AN: 157520Hom.: 0 AF XY: 0.0000240 AC XY: 2AN XY: 83228
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GnomAD4 exome AF: 0.0000236 AC: 33AN: 1399588Hom.: 0 Cov.: 31 AF XY: 0.0000203 AC XY: 14AN XY: 690294
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GnomAD4 genome AF: 0.0000197 AC: 3AN: 152212Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2AN XY: 74360
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Oct 10, 2023 | The c.1871T>C (p.M624T) alteration is located in exon 17 (coding exon 14) of the CRACR2A gene. This alteration results from a T to C substitution at nucleotide position 1871, causing the methionine (M) at amino acid position 624 to be replaced by a threonine (T). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
CADD
Uncertain
DANN
Uncertain
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Pathogenic
D
LIST_S2
Uncertain
D
M_CAP
Uncertain
D
MetaRNN
Pathogenic
D
MetaSVM
Benign
T
MutationTaster
Benign
N
PrimateAI
Uncertain
T
PROVEAN
Uncertain
D
REVEL
Uncertain
Sift
Uncertain
D
Sift4G
Uncertain
D
Polyphen
P
Vest4
MutPred
Loss of stability (P = 0.2102);
MVP
MPC
ClinPred
D
GERP RS
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at