Genetic Variant CLNK:p.Ile361Met (chr4-10501313-T-C) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_052964.4(CLNK):c.1083A>G(p.Ile361Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. I361I) has been classified as Benign.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

CLNK
NM_052964.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.610

Publications

14 publications found

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:58732):

ENSG00000287154 links:

LOC105374482 (HGNC:):

LOC105374482 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
CLNK	NM_052964.4 link	c.1083A>G	p.Ile361Met	missense_variant	Exon 18 of 19	ENST00000226951.11	NP_443196.2
CLNK	XM_011513775.3 link	c.1128A>G	p.Ile376Met	missense_variant	Exon 18 of 19		XP_011512077.1
CLNK	XM_017007684.2 link	c.1128A>G	p.Ile376Met	missense_variant	Exon 18 of 19		XP_016863173.1
LOC105374482	XR_925387.4 link	n.261+4758T>C		intron_variant	Intron 2 of 2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
CLNK	ENST00000226951.11 link	c.1083A>G	p.Ile361Met	missense_variant	Exon 18 of 19	1	NM_052964.4	ENSP00000226951.6	Q7Z7G1-1
CLNK	ENST00000515667.5 link	c.297A>G	p.Ile99Met	missense_variant	Exon 4 of 5	3		ENSP00000427256.1	D6RJB9
ENSG00000287154	ENST00000663264.1 link	n.97-28821T>C		intron_variant	Intron 1 of 2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

6.87e-7

AC:

AN:

1455132

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

723818

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

33010

American (AMR)

AF:

0.00

AC:

AN:

42898

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25980

East Asian (EAS)

AF:

0.00

AC:

AN:

39428

South Asian (SAS)

AF:

0.00

AC:

AN:

84880

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53346

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5742

European-Non Finnish (NFE)

AF:

9.01e-7

AC:

AN:

1109724

Other (OTH)

AF:

0.00

AC:

AN:

60124

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.325

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

Pathogenic

0.69

BayesDel_addAF

Pathogenic

0.34

BayesDel_noAF

Pathogenic

0.25

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.85

D;.;T

Eigen

Uncertain

0.52

Eigen_PC

Uncertain

0.44

FATHMM_MKL

Benign

0.69

LIST_S2

Benign

0.79

T;T;T

M_CAP

Uncertain

0.16

MetaRNN

Uncertain

0.69

D;D;D

MetaSVM

Uncertain

0.44

MutationAssessor

Pathogenic

4.3

H;.;.

PhyloP100

0.61

PrimateAI

Uncertain

0.65

PROVEAN

Uncertain

-2.8

D;D;.

REVEL

Pathogenic

0.73

Sift

Pathogenic

0.0

D;D;.

Sift4G

Pathogenic

0.0

D;D;D

Polyphen

1.0

D;.;.

Vest4

0.69

MutPred

0.65

Gain of MoRF binding (P = 0.0957);.;Gain of MoRF binding (P = 0.0957);

MVP

0.33

MPC

0.035

ClinPred

1.0

GERP RS

5.4

Varity_R

0.51

gMVP

0.50

Mutation Taster

=76/24

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

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over