Genetic Variant CLIP1:p.Ala1224Ser (chr12-122279123-C-A) – ACMG Classification: Benign (-16 pts)

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_StrongBP6_Very_StrongBS2

The NM_001247997.2(CLIP1):c.3670G>T(p.Ala1224Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00679 in 1,611,020 control chromosomes in the GnomAD database, including 43 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0056 ( 7 hom., cov: 32)

Exomes 𝑓: 0.0069 ( 36 hom. )

Consequence

CLIP1
NM_001247997.2 missense

Scores

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: -1.02

Publications

15 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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -16 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0024212897).

BP6

Variant 12-122279123-C-A is Benign according to our data. Variant chr12-122279123-C-A is described in ClinVar as Likely_benign. ClinVar VariationId is 788442.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS2

High Homozygotes in GnomAd4 at 7 AR gene

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.3670G>T	p.Ala1224Ser	missense	Exon 22 of 26	NP_001234926.1	P30622-3
CLIP1	NM_001389291.1		c.5800G>T	p.Ala1934Ser	missense	Exon 21 of 25	NP_001376220.1
CLIP1	NM_002956.3		c.3637G>T	p.Ala1213Ser	missense	Exon 21 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.3670G>T	p.Ala1224Ser	missense	Exon 22 of 26	ENSP00000479322.1	P30622-3
CLIP1	ENST00000358808.6	TSL:1	c.3637G>T	p.Ala1213Ser	missense	Exon 21 of 25	ENSP00000351665.2	P30622-1
CLIP1	ENST00000537178.5	TSL:1	c.3532G>T	p.Ala1178Ser	missense	Exon 20 of 24	ENSP00000445531.1	P30622-2

Frequencies

GnomAD3 genomes

AF:

0.00561

AC:

854

AN:

152144

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00167

Gnomad AMI

AF:

0.00330

Gnomad AMR

AF:

0.00779

Gnomad ASJ

AF:

0.0115

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00311

Gnomad FIN

AF:

0.0000943

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.00876

Gnomad OTH

AF:

0.00431

GnomAD2 exomes

AF:

0.00520

AC:

1288

AN:

247854

AF XY:

0.00548

show subpopulations

Gnomad AFR exome

AF:

0.00117

Gnomad AMR exome

AF:

0.00382

Gnomad ASJ exome

AF:

0.0103

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000278

Gnomad NFE exome

AF:

0.00831

Gnomad OTH exome

AF:

0.00595

GnomAD4 exome

AF:

0.00691

AC:

10083

AN:

1458758

Hom.:

Cov.:

AF XY:

0.00684

AC XY:

4965

AN XY:

725768

show subpopulations

African (AFR)

AF:

0.00123

AC:

AN:

33302

American (AMR)

AF:

0.00366

AC:

161

AN:

43948

Ashkenazi Jewish (ASJ)

AF:

0.0107

AC:

279

AN:

26036

East Asian (EAS)

AF:

0.00

AC:

AN:

39666

South Asian (SAS)

AF:

0.00246

AC:

211

AN:

85632

European-Finnish (FIN)

AF:

0.000432

AC:

AN:

53280

Middle Eastern (MID)

AF:

0.00365

AC:

AN:

5746

European-Non Finnish (NFE)

AF:

0.00803

AC:

8917

AN:

1110892

Other (OTH)

AF:

0.00714

AC:

430

AN:

60256

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.445

Heterozygous variant carriers

476

953

1429

1906

2382

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

330

660

990

1320

1650

<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

AF:

0.00561

AC:

854

AN:

152262

Hom.:

Cov.:

AF XY:

0.00502

AC XY:

374

AN XY:

74442

show subpopulations

African (AFR)

AF:

0.00166

AC:

AN:

41546

American (AMR)

AF:

0.00778

AC:

119

AN:

15288

Ashkenazi Jewish (ASJ)

AF:

0.0115

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5194

South Asian (SAS)

AF:

0.00311

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.0000943

AC:

AN:

10600

Middle Eastern (MID)

AF:

0.00680

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00876

AC:

596

AN:

68024

Other (OTH)

AF:

0.00426

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

140

187

234

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

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

Alfa

AF:

0.00745

Hom.:

Bravo

AF:

0.00595

TwinsUK

AF:

0.00890

AC:

ALSPAC

AF:

0.00675

AC:

ESP6500AA

AF:

0.00159

AC:

ESP6500EA

AF:

0.00849

AC:

ExAC

AF:

0.00488

AC:

592

Asia WGS

AF:

0.00144

AC:

AN:

3478

EpiCase

AF:

0.00966

EpiControl

AF:

0.00789

ClinVar

ClinVar submissions

Significance:Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.088

BayesDel_addAF

Benign

-0.60

BayesDel_noAF

Benign

-0.63

CADD

Benign

(source)

DANN

Benign

0.86

DEOGEN2

Benign

0.061

Eigen

Benign

-1.1

Eigen_PC

Benign

-0.98

FATHMM_MKL

Benign

0.13

LIST_S2

Benign

0.80

MetaRNN

Benign

0.0024

MetaSVM

Benign

-1.0

MutationAssessor

Benign

-0.90

PhyloP100

-1.0

PrimateAI

Benign

0.26

PROVEAN

Benign

-0.38

REVEL

Benign

0.029

Sift

Benign

0.18

Sift4G

Benign

0.74

Polyphen

0.011

Vest4

0.11

MVP

0.31

MPC

0.57

ClinPred

0.0085

GERP RS

-4.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.025

gMVP

0.089

Mutation Taster

=97/3

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over