4-10501312-G-A

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 1P and 4B. PP3 BP4_Moderate BP6_Moderate

The NM_052964.4(CLNK):c.1084C>T(p.Arg362Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00203 in 1,607,184 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R362H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0011 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0021 (4 hom.)
• Consequence: CLNK NM_052964.4 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 8.73

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]

(HGNC:):

ACMG classification

Verdict is Likely_benign. Variant got -3 ACMG points.

• PP3: Multiple lines of computational evidence support a deleterious effect 7: BayesDel_noAF, Cadd, Dann, Eigen, phyloP100way_vertebrate, PROVEAN, REVEL [when max_spliceai, FATHMM_MKL, MetaRNN, MutationTaster was below the threshold]
• BP4: Computational evidence support a benign effect (MetaRNN=0.17073885).
• BP6: Variant 4-10501312-G-A is Benign according to our data. Variant chr4-10501312-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 3052806.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CLNK	NM_052964.4	c.1084C>T	p.Arg362Cys	missense_variant	18/19	ENST00000226951.11
LOC105374482	XR_925387.4	n.261+4757G>A		intron_variant, non_coding_transcript_variant
CLNK	XM_011513775.3	c.1129C>T	p.Arg377Cys	missense_variant	18/19
CLNK	XM_017007684.2	c.1129C>T	p.Arg377Cys	missense_variant	18/19

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CLNK	ENST00000226951.11	c.1084C>T	p.Arg362Cys	missense_variant	18/19	1	NM_052964.4	P1
	ENST00000663264.1	n.97-28822G>A		intron_variant, non_coding_transcript_variant
CLNK	ENST00000515667.5	c.298C>T	p.Arg100Cys	missense_variant	4/5	3

Frequencies

GnomAD3 genomes AF: 0.00113 AC: 172 AN: 152158 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000531

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

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: 0.00218

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000940 AC: 228 AN: 242428 Hom.: 1 AF XY: 0.00105 AC XY: 138 AN XY: 131840

Gnomad AFR exome AF: 0.000330

Gnomad AMR exome AF: 0.000188

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000574

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00189

Gnomad OTH exome AF: 0.00103

GnomAD4 exome AF: 0.00213 AC: 3092 AN: 1454908 Hom.: 4 Cov.: 30 AF XY: 0.00199 AC XY: 1439 AN XY: 723714

Gnomad4 AFR exome AF: 0.000455

Gnomad4 AMR exome AF: 0.000186

Gnomad4 ASJ exome AF: 0.0000770

Gnomad4 EAS exome AF: 0.0000508

Gnomad4 SAS exome AF: 0.0000118

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00267

Gnomad4 OTH exome AF: 0.00165

GnomAD4 genome AF: 0.00113 AC: 172 AN: 152276 Hom.: 0 Cov.: 33 AF XY: 0.00109 AC XY: 81 AN XY: 74448

Gnomad4 AFR AF: 0.000529

Gnomad4 AMR AF: 0.0000654

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00218

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.00182 Hom.: 0

Bravo AF: 0.00101

ExAC AF: 0.00104 AC: 126

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.00230

EpiControl AF: 0.00239

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

CLNK-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 10, 2022

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.53
BayesDel_addAF	Uncertain	0.14	D
BayesDel_noAF	Pathogenic	0.42
Cadd	Pathogenic	33
Dann	Pathogenic	1.0
DEOGEN2	Uncertain	0.71	D;.;T
Eigen	Pathogenic	0.83
Eigen_PC	Pathogenic	0.81
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.91	D;D;D
MetaRNN	Benign	0.17	T;T;T
MetaSVM	Uncertain	0.59	D
MutationAssessor	Uncertain	2.5	M;.;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.68	T
PROVEAN	Pathogenic	-6.9	D;D;.
REVEL	Pathogenic	0.92
Sift	Pathogenic	0.0	D;D;.
Sift4G	Pathogenic	0.0	D;D;D
Polyphen		1.0	D;.;.
Vest4		0.93
MVP		0.58
MPC		0.031
ClinPred		0.12	T
GERP RS		5.4
Varity_R		0.74
gMVP		0.52

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

Other links and lift over

dbSNP: rs190441710; hg19: chr4-10502936;