chr2-167210841-G-A
Variant summary
Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PVS1PM2
The ENST00000409273.6(XIRP2):c.3G>A(p.Met1?) variant causes a start lost change. The variant allele was found at a frequency of 0.00000137 in 1,461,868 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).
Frequency
Genomes: not found (cov: 32)
Exomes 𝑓: 0.0000014 ( 0 hom. )
Consequence
XIRP2
ENST00000409273.6 start_lost
ENST00000409273.6 start_lost
Scores
5
7
5
Clinical Significance
Conservation
PhyloP100: 6.59
Genes affected
XIRP2 (HGNC:14303): (xin actin binding repeat containing 2) Enables actin filament binding activity. Predicted to be involved in actin cytoskeleton organization and heart development. Predicted to act upstream of or within cardiac muscle tissue morphogenesis; cell-cell junction organization; and ventricular septum development. Colocalizes with focal adhesion and stress fiber. [provided by Alliance of Genome Resources, Apr 2022]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 10 ACMG points.
PVS1
?
Start lost variant, no new inframe start found.
PM2
?
Very rare variant in population databases, with high coverage;
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
XIRP2 | NM_152381.6 | c.669G>A | p.Met223Ile | missense_variant | 4/11 | ENST00000409195.6 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
XIRP2 | ENST00000409195.6 | c.669G>A | p.Met223Ile | missense_variant | 4/11 | 5 | NM_152381.6 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD3 genomes
?
Cov.:
32
GnomAD3 exomes AF: 0.00000401 AC: 1AN: 249552Hom.: 0 AF XY: 0.00000739 AC XY: 1AN XY: 135390
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GnomAD4 exome AF: 0.00000137 AC: 2AN: 1461868Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1AN XY: 727240
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GnomAD4 genome ? Cov.: 32
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?
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32
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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 | May 17, 2023 | The c.669G>A (p.M223I) alteration is located in exon 4 (coding exon 3) of the XIRP2 gene. This alteration results from a G to A substitution at nucleotide position 669, causing the methionine (M) at amino acid position 223 to be replaced by an isoleucine (I). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
Cadd
Pathogenic
Dann
Uncertain
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Uncertain
D
LIST_S2
Benign
T;T;D;D;D;D
M_CAP
Benign
D
MetaRNN
Uncertain
D;D;D;D;D;D
MetaSVM
Uncertain
D
MutationTaster
Benign
D;D;D;D;D;D;D;D
PrimateAI
Uncertain
T
PROVEAN
Uncertain
D;D;N;.;N;N
REVEL
Benign
Sift
Uncertain
D;D;D;.;D;D
Sift4G
Benign
T;D;.;.;.;T
Polyphen
D;D;.;D;D;.
Vest4
MutPred
0.36
.;.;.;Loss of catalytic residue at M48 (P = 0.0243);.;.;
MVP
MPC
0.15
ClinPred
D
GERP RS
Varity_R
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