4-10501299-C-T

Variant names:

• chr4-10501299-C-T
• NM_052964.4:c.1097G>A

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_052964.4(CLNK):​c.1097G>A​(p.Arg366Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: CLNK NM_052964.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.169

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]

ENSG00000287154 (HGNC:):

ACMG classification

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=0.030635417).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CLNK	NM_052964.4	c.1097G>A	p.Arg366Lys	missense_variant	Exon 18 of 19	ENST00000226951.11	NP_443196.2
CLNK	XM_011513775.3	c.1142G>A	p.Arg381Lys	missense_variant	Exon 18 of 19		XP_011512077.1
CLNK	XM_017007684.2	c.1142G>A	p.Arg381Lys	missense_variant	Exon 18 of 19		XP_016863173.1
LOC105374482	XR_925387.4	n.261+4744C>T		intron_variant	Intron 2 of 2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CLNK	ENST00000226951.11	c.1097G>A	p.Arg366Lys	missense_variant	Exon 18 of 19	1	NM_052964.4	ENSP00000226951.6
CLNK	ENST00000515667.5	c.311G>A	p.Arg104Lys	missense_variant	Exon 4 of 5	3		ENSP00000427256.1
ENSG00000287154	ENST00000663264.1	n.97-28835C>T		intron_variant	Intron 1 of 2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jan 04, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1097G>A (p.R366K) 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 1097, causing the arginine (R) at amino acid position 366 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	0.070
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Benign	-0.47
CADD	Benign	8.4
DANN	Benign	0.95
DEOGEN2	Benign	0.17	T;.;T
Eigen	Benign	-0.74
Eigen_PC	Benign	-0.63
FATHMM_MKL	Benign	0.045	N
LIST_S2	Benign	0.25	T;T;T
M_CAP	Benign	0.011	T
MetaRNN	Benign	0.031	T;T;T
MetaSVM	Benign	-0.75	T
MutationAssessor	Benign	0.73	N;.;.
PrimateAI	Benign	0.30	T
PROVEAN	Benign	-0.41	N;N;.
REVEL	Benign	0.15
Sift	Benign	0.37	T;T;.
Sift4G	Benign	0.89	T;T;T
Polyphen		0.0020	B;.;.
Vest4		0.057
MutPred		0.33		Gain of ubiquitination at R366 (P = 0.0592);.;Gain of ubiquitination at R366 (P = 0.0592);
MVP		0.16
MPC		0.0066
ClinPred		0.88	D
GERP RS		1.6
Varity_R		0.068
gMVP		0.19

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr4-10502923;