chr4-10501258-C-T

Position:

chr4-10501258-C-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_052964.4(CLNK):c.1138G>A(p.Glu380Lys) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000592 in 1,570,126 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/23 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00037 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000026 ( 0 hom. )

Consequence

CLNK
NM_052964.4 missense, splice_region

Scores

Splicing: ADA: 0.01047

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.641

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:

(HGNC:):

links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.033815622).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
CLNK	NM_052964.4 linkuse as main transcript	c.1138G>A	p.Glu380Lys	missense_variant, splice_region_variant	18/19	ENST00000226951.11
LOC105374482	XR_925387.4 linkuse as main transcript	n.261+4703C>T		intron_variant, non_coding_transcript_variant
CLNK	XM_011513775.3 linkuse as main transcript	c.1183G>A	p.Glu395Lys	missense_variant, splice_region_variant	18/19
CLNK	XM_017007684.2 linkuse as main transcript	c.1183G>A	p.Glu395Lys	missense_variant, splice_region_variant	18/19

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CLNK	ENST00000226951.11 linkuse as main transcript	c.1138G>A	p.Glu380Lys	missense_variant, splice_region_variant	18/19	1	NM_052964.4	P1	Q7Z7G1-1
	ENST00000663264.1 linkuse as main transcript	n.97-28876C>T		intron_variant, non_coding_transcript_variant
CLNK	ENST00000515667.5 linkuse as main transcript	c.352G>A	p.Glu118Lys	missense_variant, splice_region_variant	4/5	3

Frequencies

GnomAD3 genomes

AF:

0.000368

AC:

AN:

152246

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00366

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000133

AC:

AN:

210174

Hom.:

AF XY:

0.0000955

AC XY:

AN XY:

115240

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00127

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000261

AC:

AN:

1417880

Hom.:

Cov.:

AF XY:

0.0000185

AC XY:

AN XY:

704424

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00115

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:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.000368

AC:

AN:

152246

Hom.:

Cov.:

AF XY:

0.000578

AC XY:

AN XY:

74386

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00366

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.000253

ExAC

AF:

0.0000165

AC:

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

Aug 30, 2022

The c.1138G>A (p.E380K) alteration is located in exon 18 (coding exon 17) of the CLNK gene. This alteration results from a G to A substitution at nucleotide position 1138, causing the glutamic acid (E) at amino acid position 380 to be replaced by a lysine (K). 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

0.16

BayesDel_addAF

Benign

-0.32

BayesDel_noAF

Benign

-0.27

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.58

D;.;T

Eigen

Benign

-0.31

Eigen_PC

Benign

-0.26

FATHMM_MKL

Benign

0.52

LIST_S2

Benign

0.82

T;T;T

M_CAP

Benign

0.052

MetaRNN

Benign

0.034

T;T;T

MetaSVM

Uncertain

-0.060

MutationAssessor

Benign

1.6

L;.;.

MutationTaster

Benign

0.99

D;D

PrimateAI

Benign

0.39

PROVEAN

Uncertain

-3.4

D;D;.

REVEL

Benign

0.25

Sift

Uncertain

0.0020

D;D;.

Sift4G

Uncertain

0.029

D;D;D

Polyphen

0.13

B;.;.

Vest4

0.18

MutPred

0.60

Gain of ubiquitination at E380 (P = 0.0258);.;Gain of ubiquitination at E380 (P = 0.0258);

MVP

0.30

MPC

0.0074

ClinPred

0.19

GERP RS

3.6

Varity_R

0.35

gMVP

0.31

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.010

dbscSNV1_RF

Benign

0.11

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