chr12-3627631-T-C
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Variant summary
Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1PM2PP3_Strong
The NM_001144958.2(CRACR2A):āc.1811A>Gā(p.Gln604Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000406 in 1,551,602 control chromosomes in the GnomAD database, including 1 homozygotes. 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: 0.000043 ( 1 hom. )
Consequence
CRACR2A
NM_001144958.2 missense
NM_001144958.2 missense
Scores
9
6
2
Clinical Significance
Conservation
PhyloP100: 7.63
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 Likely_pathogenic. Variant got 8 ACMG points.
PM1
In a mutagenesis_site GTP-binding mutant with reduced GTPase activity but increased protein stability. Increased ability to activate JNK signaling pathway. No effect on its localization to the microtubule organizing center or Golgi apparatus membrane. (size 0) in uniprot entity EFC4B_HUMAN
PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.949
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CRACR2A | NM_001144958.2 | c.1811A>G | p.Gln604Arg | missense_variant | 16/20 | ENST00000440314.7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CRACR2A | ENST00000440314.7 | c.1811A>G | p.Gln604Arg | missense_variant | 16/20 | 2 | NM_001144958.2 | P1 | |
CRACR2A | ENST00000333750.9 | c.*808A>G | 3_prime_UTR_variant, NMD_transcript_variant | 10/15 | 2 |
Frequencies
GnomAD3 genomes AF: 0.0000197 AC: 3AN: 152194Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000959 AC: 15AN: 156452Hom.: 0 AF XY: 0.000109 AC XY: 9AN XY: 82926
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GnomAD4 exome AF: 0.0000429 AC: 60AN: 1399408Hom.: 1 Cov.: 36 AF XY: 0.0000377 AC XY: 26AN XY: 690208
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GnomAD4 genome AF: 0.0000197 AC: 3AN: 152194Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1AN XY: 74356
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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 | Mar 31, 2023 | The c.1811A>G (p.Q604R) alteration is located in exon 16 (coding exon 13) of the CRACR2A gene. This alteration results from a A to G substitution at nucleotide position 1811, causing the glutamine (Q) at amino acid position 604 to be replaced by an arginine (R). 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
Uncertain
CADD
Pathogenic
DANN
Uncertain
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
LIST_S2
Pathogenic
D
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D
MetaSVM
Uncertain
D
MutationTaster
Benign
D
PrimateAI
Uncertain
T
PROVEAN
Uncertain
D
REVEL
Pathogenic
Sift
Pathogenic
D
Sift4G
Pathogenic
D
Polyphen
D
Vest4
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