chr4-10584947-G-A

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_052964.4(CLNK):c.92C>T(p.Pro31Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0523 in 1,613,330 control chromosomes in the GnomAD database, including 2,511 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P31S) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.041 ( 187 hom., cov: 32)

Exomes 𝑓: 0.053 ( 2324 hom. )

Consequence

CLNK
NM_052964.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 1.92

Publications

6 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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0022577345).

BP6

Variant 4-10584947-G-A is Benign according to our data. Variant chr4-10584947-G-A is described in ClinVar as Benign. ClinVar VariationId is 402545.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0574 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
CLNK	NM_052964.4 link	c.92C>T	p.Pro31Leu	missense_variant	Exon 4 of 19	ENST00000226951.11	NP_443196.2
CLNK	XM_011513775.3 link	c.137C>T	p.Pro46Leu	missense_variant	Exon 4 of 19		XP_011512077.1
CLNK	XM_017007684.2 link	c.137C>T	p.Pro46Leu	missense_variant	Exon 4 of 19		XP_016863173.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CLNK	ENST00000226951.11 link	c.92C>T	p.Pro31Leu	missense_variant	Exon 4 of 19	1	NM_052964.4	ENSP00000226951.6		Q7Z7G1-1
CLNK	ENST00000507719.1 link	c.-35C>T		5_prime_UTR_variant	Exon 4 of 13	1		ENSP00000427208.1		Q7Z7G1-2

Frequencies

GnomAD3 genomes

AF:

0.0407

AC:

6190

AN:

152116

Hom.:

186

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0150

Gnomad AMI

AF:

0.0866

Gnomad AMR

AF:

0.0384

Gnomad ASJ

AF:

0.0576

Gnomad EAS

AF:

0.000770

Gnomad SAS

AF:

0.0342

Gnomad FIN

AF:

0.0367

Gnomad MID

AF:

0.0886

Gnomad NFE

AF:

0.0589

Gnomad OTH

AF:

0.0530

GnomAD2 exomes

AF:

0.0432

AC:

10731

AN:

248444

AF XY:

0.0454

show subpopulations

Gnomad AFR exome

AF:

0.0136

Gnomad AMR exome

AF:

0.0341

Gnomad ASJ exome

AF:

0.0566

Gnomad EAS exome

AF:

0.000279

Gnomad FIN exome

AF:

0.0400

Gnomad NFE exome

AF:

0.0570

Gnomad OTH exome

AF:

0.0499

GnomAD4 exome

AF:

0.0535

AC:

78149

AN:

1461096

Hom.:

2324

Cov.:

AF XY:

0.0538

AC XY:

39134

AN XY:

726774

show subpopulations

African (AFR)

AF:

0.0146

AC:

488

AN:

33468

American (AMR)

AF:

0.0349

AC:

1562

AN:

44694

Ashkenazi Jewish (ASJ)

AF:

0.0577

AC:

1507

AN:

26128

East Asian (EAS)

AF:

0.000227

AC:

AN:

39694

South Asian (SAS)

AF:

0.0394

AC:

3394

AN:

86114

European-Finnish (FIN)

AF:

0.0386

AC:

2060

AN:

53386

Middle Eastern (MID)

AF:

0.0619

AC:

357

AN:

5764

European-Non Finnish (NFE)

AF:

0.0593

AC:

65890

AN:

1111488

Other (OTH)

AF:

0.0477

AC:

2882

AN:

60360

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.457

Heterozygous variant carriers

3623

7246

10869

14492

18115

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

2426

4852

7278

9704

12130

<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:

0.0407

AC:

6190

AN:

152234

Hom.:

187

Cov.:

AF XY:

0.0405

AC XY:

3012

AN XY:

74430

show subpopulations

African (AFR)

AF:

0.0150

AC:

621

AN:

41530

American (AMR)

AF:

0.0383

AC:

586

AN:

15300

Ashkenazi Jewish (ASJ)

AF:

0.0576

AC:

200

AN:

3472

East Asian (EAS)

AF:

0.000772

AC:

AN:

5184

South Asian (SAS)

AF:

0.0342

AC:

165

AN:

4818

European-Finnish (FIN)

AF:

0.0367

AC:

389

AN:

10588

Middle Eastern (MID)

AF:

0.0986

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0589

AC:

4006

AN:

68020

Other (OTH)

AF:

0.0525

AC:

111

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

295

590

885

1180

1475

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

140

210

280

350

<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:

0.0521

Hom.:

490

Bravo

AF:

0.0402

TwinsUK

AF:

0.0596

AC:

221

ALSPAC

AF:

0.0651

AC:

251

ESP6500AA

AF:

0.0118

AC:

ESP6500EA

AF:

0.0617

AC:

515

ExAC

AF:

0.0426

AC:

5155

Asia WGS

AF:

0.0150

AC:

AN:

3478

EpiCase

AF:

0.0638

EpiControl

AF:

0.0623

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:1

Mar 29, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency -

not provided

Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.19

BayesDel_addAF

Benign

-0.53

BayesDel_noAF

Benign

-0.48

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.38

T;T

Eigen

Benign

0.14

Eigen_PC

Benign

0.084

FATHMM_MKL

Uncertain

0.81

LIST_S2

Benign

0.58

T;T

MetaRNN

Benign

0.0023

T;T

MetaSVM

Benign

-1.2

MutationAssessor

Benign

1.3

L;.

PhyloP100

1.9

PrimateAI

Benign

0.38

PROVEAN

Uncertain

-2.6

D;.

REVEL

Benign

0.12

Sift

Uncertain

0.0010

D;.

Sift4G

Uncertain

0.0090

D;D

Polyphen

0.99

D;.

Vest4

0.15

MPC

0.0065

ClinPred

0.027

GERP RS

3.9

Varity_R

0.13

gMVP

0.064

Mutation Taster

=94/6

polymorphism (auto)

(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

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over