7-74338708-C-G

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2PP3_Strong

The NM_003388.5(CLIP2):​c.382C>G​(p.Arg128Gly) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic 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. R128S) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Consequence

CLIP2
NM_003388.5 missense

Scores

14
4
1

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 5.82

Publications

0 publications found
Variant links:
Genes affected
CLIP2 (HGNC:2586): (CAP-Gly domain containing linker protein 2) The protein encoded by this gene belongs to the family of cytoplasmic linker proteins, which have been proposed to mediate the interaction between specific membranous organelles and microtubules. This protein was found to associate with both microtubules and an organelle called the dendritic lamellar body. This gene is hemizygously deleted in Williams syndrome, a multisystem developmental disorder caused by the deletion of contiguous genes at 7q11.23. Alternative splicing of this gene generates 2 transcript variants. [provided by RefSeq, Jul 2008]

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ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.984

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
CLIP2NM_003388.5 linkc.382C>G p.Arg128Gly missense_variant Exon 3 of 17 ENST00000223398.11 NP_003379.4 Q9UDT6-1A0A140VJG6
CLIP2NM_032421.3 linkc.382C>G p.Arg128Gly missense_variant Exon 3 of 16 NP_115797.2 Q9UDT6-2A7E2F7
CLIP2XM_047420800.1 linkc.382C>G p.Arg128Gly missense_variant Exon 3 of 13 XP_047276756.1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
CLIP2ENST00000223398.11 linkc.382C>G p.Arg128Gly missense_variant Exon 3 of 17 5 NM_003388.5 ENSP00000223398.6 Q9UDT6-1
CLIP2ENST00000361545.9 linkc.382C>G p.Arg128Gly missense_variant Exon 3 of 16 1 ENSP00000355151.5 Q9UDT6-2

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
33
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Apr 12, 2023
Ambry Genetics
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

The c.382C>G (p.R128G) alteration is located in exon 3 (coding exon 2) of the CLIP2 gene. This alteration results from a C to G substitution at nucleotide position 382, causing the arginine (R) at amino acid position 128 to be replaced by a glycine (G). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.76
BayesDel_addAF
Pathogenic
0.47
D
BayesDel_noAF
Pathogenic
0.43
CADD
Pathogenic
28
DANN
Uncertain
1.0
DEOGEN2
Pathogenic
0.92
.;D;D
Eigen
Pathogenic
0.96
Eigen_PC
Pathogenic
0.85
FATHMM_MKL
Uncertain
0.95
D
LIST_S2
Uncertain
0.95
D;D;.
M_CAP
Pathogenic
0.67
D
MetaRNN
Pathogenic
0.98
D;D;D
MetaSVM
Pathogenic
1.1
D
MutationAssessor
Pathogenic
3.8
H;H;H
PhyloP100
5.8
PrimateAI
Uncertain
0.78
T
PROVEAN
Pathogenic
-5.8
D;D;D
REVEL
Pathogenic
0.94
Sift
Pathogenic
0.0
D;D;D
Sift4G
Pathogenic
0.0010
D;D;D
Polyphen
1.0
D;D;D
Vest4
0.93
MutPred
0.89
Loss of methylation at R128 (P = 0.0815);Loss of methylation at R128 (P = 0.0815);Loss of methylation at R128 (P = 0.0815);
MVP
0.94
MPC
1.0
ClinPred
0.99
D
GERP RS
4.8
Varity_R
0.94
gMVP
0.94
Mutation Taster
=19/81
disease causing

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

Publications

Other links and lift over

dbSNP: rs1332276102; hg19: chr7-73753038; API