Variant chr4-10508034-A-C details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_052964.4(CLNK):c.909T>G(p.Asp303Glu) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000657 in 152,270 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Consequence

CLNK
NM_052964.4 missense, splice_region

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.246

Variant links:

Genes affected

CLNK (HGNC:17438): (cytokine dependent hematopoietic cell linker) MIST is a member of the SLP76 family of adaptors (see LCP2, MIM 601603; BLNK, MIM 604515). MIST plays a role in the regulation of immunoreceptor signaling, including PLC-gamma (PLCG1; MIM 172420)-mediated B cell antigen receptor (BCR) signaling and FC-epsilon R1 (see FCER1A, MIM 147140)-mediated mast cell degranulation (Cao et al., 1999 [PubMed 10562326]; Goitsuka et al., 2000, 2001 [PubMed 10744659] [PubMed 11463797]).[supplied by OMIM, Mar 2008]

CLNK links:

ENSG00000287154 (HGNC:):

ENSG00000287154 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.07713896).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
CLNK	NM_052964.4 linkuse as main transcript	c.909T>G	p.Asp303Glu	missense_variant, splice_region_variant	17/19	ENST00000226951.11	NP_443196.2
CLNK	XM_011513775.3 linkuse as main transcript	c.954T>G	p.Asp318Glu	missense_variant, splice_region_variant	17/19		XP_011512077.1
CLNK	XM_017007684.2 linkuse as main transcript	c.954T>G	p.Asp318Glu	missense_variant, splice_region_variant	17/19		XP_016863173.1
LOC105374482	XR_925387.4 linkuse as main transcript	n.261+11479A>C		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
CLNK	ENST00000226951.11 linkuse as main transcript	c.909T>G	p.Asp303Glu	missense_variant, splice_region_variant	17/19	1	NM_052964.4	ENSP00000226951.6	Q7Z7G1-1
CLNK	ENST00000515667.5 linkuse as main transcript	c.123T>G	p.Asp41Glu	missense_variant, splice_region_variant	3/5	3		ENSP00000427256.1	D6RJB9
ENSG00000287154	ENST00000663264.1 linkuse as main transcript	n.97-22100A>C		intron_variant

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152270

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD4 exome

Cov.:

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152270

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74402

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

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

Apr 15, 2024

The c.909T>G (p.D303E) alteration is located in exon 17 (coding exon 16) of the CLNK gene. This alteration results from a T to G substitution at nucleotide position 909, causing the aspartic acid (D) at amino acid position 303 to be replaced by a glutamic acid (E). 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

Benign

0.14

BayesDel_addAF

Benign

-0.28

BayesDel_noAF

Benign

-0.63

CADD

Benign

0.10

DANN

Benign

0.86

DEOGEN2

Benign

0.16

T;.;T

Eigen

Benign

-1.3

Eigen_PC

Benign

-1.4

FATHMM_MKL

Benign

0.018

LIST_S2

Benign

0.50

T;T;T

M_CAP

Benign

0.013

MetaRNN

Benign

0.077

T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.81

L;.;.

PrimateAI

Benign

0.31

PROVEAN

Benign

-2.0

N;N;.

REVEL

Benign

0.098

Sift

Benign

0.046

D;T;.

Sift4G

Benign

0.20

T;T;T

Polyphen

0.051

B;.;.

Vest4

0.17

MutPred

0.24

Loss of ubiquitination at K302 (P = 0.0777);.;Loss of ubiquitination at K302 (P = 0.0777);

MVP

0.030

MPC

0.0075

ClinPred

0.10

GERP RS

-8.2

Varity_R

0.057

gMVP

0.13

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