Variant 7-74338738-A-C details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_003388.5(CLIP2):c.412A>C(p.Ile138Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000138 in 1,446,006 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

CLIP2
NM_003388.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.27

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 made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
CLIP2	NM_003388.5 linkuse as main transcript	c.412A>C	p.Ile138Leu	missense_variant	3/17	ENST00000223398.11	NP_003379.4
CLIP2	NM_032421.3 linkuse as main transcript	c.412A>C	p.Ile138Leu	missense_variant	3/16		NP_115797.2
CLIP2	XM_047420800.1 linkuse as main transcript	c.412A>C	p.Ile138Leu	missense_variant	3/13		XP_047276756.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CLIP2	ENST00000223398.11 linkuse as main transcript	c.412A>C	p.Ile138Leu	missense_variant	3/17	5	NM_003388.5	ENSP00000223398	P3	Q9UDT6-1
CLIP2	ENST00000361545.9 linkuse as main transcript	c.412A>C	p.Ile138Leu	missense_variant	3/16	1		ENSP00000355151	A1	Q9UDT6-2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000138

AC:

AN:

1446006

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

718696

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000181

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Bravo

AF:

0.00000756

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

Dec 08, 2023

The c.412A>C (p.I138L) alteration is located in exon 3 (coding exon 2) of the CLIP2 gene. This alteration results from a A to C substitution at nucleotide position 412, causing the isoleucine (I) at amino acid position 138 to be replaced by a leucine (L). 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

0.83

BayesDel_addAF

Uncertain

0.13

BayesDel_noAF

Uncertain

-0.040

CADD

Uncertain

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.61

.;D;D

Eigen

Uncertain

0.52

Eigen_PC

Uncertain

0.53

FATHMM_MKL

Uncertain

0.94

LIST_S2

Uncertain

0.95

D;D;.

M_CAP

Uncertain

0.11

MetaRNN

Uncertain

0.74

D;D;D

MetaSVM

Uncertain

0.50

MutationAssessor

Benign

0.085

N;N;N

MutationTaster

Benign

1.0

D;D;D

PrimateAI

Pathogenic

0.83

PROVEAN

Benign

-1.7

N;N;N

REVEL

Pathogenic

0.73

Sift

Benign

0.097

T;T;T

Sift4G

Uncertain

0.0070

D;D;D

Polyphen

0.99

D;D;D

Vest4

0.68

MutPred

0.58

Gain of disorder (P = 0.0667);Gain of disorder (P = 0.0667);Gain of disorder (P = 0.0667);

MVP

0.81

MPC

0.92

ClinPred

0.88

GERP RS

4.8

Varity_R

0.35

gMVP

0.76

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over