Variant 4-10520793-C-G 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.770G>C(p.Arg257Thr) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000688 in 1,452,918 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/23 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: not found (cov: 33)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

CLNK
NM_052964.4 missense, splice_region

Scores

Splicing: ADA: 0.0002885

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.155

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:

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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=0.10142046).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
CLNK	NM_052964.4 linkuse as main transcript	c.770G>C	p.Arg257Thr	missense_variant, splice_region_variant	15/19	ENST00000226951.11
LOC105374482	XR_925387.4 linkuse as main transcript	n.262-9337C>G		intron_variant, non_coding_transcript_variant
CLNK	XM_011513775.3 linkuse as main transcript	c.815G>C	p.Arg272Thr	missense_variant, splice_region_variant	15/19
CLNK	XM_017007684.2 linkuse as main transcript	c.815G>C	p.Arg272Thr	missense_variant, splice_region_variant	15/19

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CLNK	ENST00000226951.11 linkuse as main transcript	c.770G>C	p.Arg257Thr	missense_variant, splice_region_variant	15/19	1	NM_052964.4	P1	Q7Z7G1-1
	ENST00000663264.1 linkuse as main transcript	n.97-9341C>G		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.88e-7

AC:

AN:

1452918

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

722456

show subpopulations

Gnomad4 AFR exome

AF:

0.0000300

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:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

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

Feb 21, 2024

The c.770G>C (p.R257T) alteration is located in exon 15 (coding exon 14) of the CLNK gene. This alteration results from a G to C substitution at nucleotide position 770, causing the arginine (R) at amino acid position 257 to be replaced by a threonine (T). 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

0.095

BayesDel_addAF

Benign

-0.097

BayesDel_noAF

Benign

-0.38

CADD

Benign

DANN

Benign

0.96

DEOGEN2

Benign

0.096

T;T

Eigen

Benign

-0.29

Eigen_PC

Benign

-0.35

FATHMM_MKL

Benign

0.20

LIST_S2

Benign

0.63

T;T

M_CAP

Benign

0.0081

MetaRNN

Benign

0.10

T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

2.0

M;.

MutationTaster

Benign

0.76

PrimateAI

Benign

0.27

PROVEAN

Benign

-1.1

N;.

REVEL

Benign

0.10

Sift

Uncertain

0.0010

D;.

Sift4G

Uncertain

0.028

D;D

Polyphen

0.96

D;.

Vest4

0.24

MutPred

0.28

Gain of phosphorylation at R257 (P = 0.072);Gain of phosphorylation at R257 (P = 0.072);

MVP

0.048

MPC

0.025

ClinPred

0.59

GERP RS

2.7

Varity_R

0.16

gMVP

0.35

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.00029

dbscSNV1_RF

Benign

0.010

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over