Genetic Variant CLIP1:p.Ser1189Arg (chr12-122309789-G-T) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_001247997.2(CLIP1):c.3567C>A(p.Ser1189Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000548 in 1,460,784 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. S1189S) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000055 ( 0 hom. )

Consequence

CLIP1
NM_001247997.2 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 3.28

Publications

1 publications found

Variant links:

Genes affected

CLIP1 (HGNC:10461): (CAP-Gly domain containing linker protein 1) The protein encoded by this gene links endocytic vesicles to microtubules. This gene is highly expressed in Reed-Sternberg cells of Hodgkin disease. Several transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Oct 2011]

CLIP1 Gene-Disease associations (from GenCC):

autosomal recessive non-syndromic intellectual disability
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
intellectual disability
Inheritance: AR Classification: LIMITED Submitted by: Ambry Genetics

CLIP1 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.13624701).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001247997.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CLIP1	NM_001247997.2	MANE Select	c.3567C>A	p.Ser1189Arg	missense	Exon 20 of 26	NP_001234926.1	P30622-3
CLIP1	NM_001389291.1		c.5697C>A	p.Ser1899Arg	missense	Exon 19 of 25	NP_001376220.1
CLIP1	NM_002956.3		c.3534C>A	p.Ser1178Arg	missense	Exon 19 of 25	NP_002947.1	P30622-1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CLIP1	ENST00000620786.5	TSL:5 MANE Select	c.3567C>A	p.Ser1189Arg	missense	Exon 20 of 26	ENSP00000479322.1	P30622-3
CLIP1	ENST00000358808.6	TSL:1	c.3534C>A	p.Ser1178Arg	missense	Exon 19 of 25	ENSP00000351665.2	P30622-1
CLIP1	ENST00000537178.5	TSL:1	c.3429C>A	p.Ser1143Arg	missense	Exon 18 of 24	ENSP00000445531.1	P30622-2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000398

AC:

AN:

251442

AF XY:

0.00000736

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000879

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000548

AC:

AN:

1460784

Hom.:

Cov.:

AF XY:

0.00000550

AC XY:

AN XY:

726718

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33446

American (AMR)

AF:

0.00

AC:

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86204

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53420

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4844

European-Non Finnish (NFE)

AF:

0.00000719

AC:

AN:

1112006

Other (OTH)

AF:

0.00

AC:

AN:

60306

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.481

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.56

BayesDel_addAF

Benign

-0.053

BayesDel_noAF

Benign

-0.31

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.17

Eigen

Benign

-0.31

Eigen_PC

Benign

-0.099

FATHMM_MKL

Uncertain

0.88

LIST_S2

Uncertain

0.87

M_CAP

Benign

0.010

MetaRNN

Benign

0.14

MetaSVM

Benign

-1.1

MutationAssessor

Benign

2.0

PhyloP100

3.3

PrimateAI

Uncertain

0.61

PROVEAN

Benign

-1.7

REVEL

Benign

0.14

Sift

Pathogenic

0.0

Sift4G

Benign

0.54

Polyphen

0.0040

Vest4

0.60

MutPred

0.27

Loss of phosphorylation at S1189 (P = 0.0072)

MVP

0.47

MPC

0.68

ClinPred

0.49

GERP RS

4.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.27

gMVP

0.47

Mutation Taster

=82/18

polymorphism

(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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over