Genetic Variant CLIP2:p.Arg128Cys (chr7-74338708-C-T) – ACMG Classification: Likely_pathogenic (6 pts)

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>T(p.Arg128Cys) variant causes a missense change. The variant allele was found at a frequency of 0.00000139 in 1,435,106 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R128G) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

CLIP2
NM_003388.5 missense

Scores

Clinical Significance

Not reported in ClinVar

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]

CLIP2 links:

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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, 0.981

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CLIP2	NM_003388.5 link	c.382C>T	p.Arg128Cys	missense_variant	Exon 3 of 17	ENST00000223398.11	NP_003379.4	Q9UDT6-1A0A140VJG6
CLIP2	NM_032421.3 link	c.382C>T	p.Arg128Cys	missense_variant	Exon 3 of 16		NP_115797.2	Q9UDT6-2A7E2F7
CLIP2	XM_047420800.1 link	c.382C>T	p.Arg128Cys	missense_variant	Exon 3 of 13		XP_047276756.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CLIP2	ENST00000223398.11 link	c.382C>T	p.Arg128Cys	missense_variant	Exon 3 of 17	5	NM_003388.5	ENSP00000223398.6		Q9UDT6-1
CLIP2	ENST00000361545.9 link	c.382C>T	p.Arg128Cys	missense_variant	Exon 3 of 16	1		ENSP00000355151.5		Q9UDT6-2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000139

AC:

AN:

1435106

Hom.:

Cov.:

AF XY:

0.00000140

AC XY:

AN XY:

712610

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33032

American (AMR)

AF:

0.0000241

AC:

AN:

41410

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25716

East Asian (EAS)

AF:

0.00

AC:

AN:

38350

South Asian (SAS)

AF:

0.00

AC:

AN:

83814

European-Finnish (FIN)

AF:

0.00

AC:

AN:

44830

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5636

European-Non Finnish (NFE)

AF:

9.07e-7

AC:

AN:

1102788

Other (OTH)

AF:

0.00

AC:

AN:

59530

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.375

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.34

BayesDel_addAF

Pathogenic

0.36

BayesDel_noAF

Pathogenic

0.28

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.95

.;D;D

Eigen

Pathogenic

0.94

Eigen_PC

Pathogenic

0.83

FATHMM_MKL

Uncertain

0.94

LIST_S2

Pathogenic

0.98

D;D;.

M_CAP

Pathogenic

0.66

MetaRNN

Pathogenic

0.98

D;D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

3.4

M;M;M

PhyloP100

5.8

PrimateAI

Pathogenic

0.82

PROVEAN

Pathogenic

-6.4

D;D;D

REVEL

Pathogenic

0.92

Sift

Pathogenic

0.0

D;D;D

Sift4G

Pathogenic

0.0

D;D;D

Polyphen

1.0

D;D;D

Vest4

0.95

MutPred

0.87

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

0.91

MPC

2.0

ClinPred

1.0

GERP RS

4.8

Varity_R

0.80

gMVP

0.90

Mutation Taster

=26/74

disease causing

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over