4-10501289-C-G

Position:

• chr4-10501289-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_052964.4(CLNK):​c.1107G>C​(p.Gln369His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000689 in 1,450,558 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: CLNK NM_052964.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.56

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 Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.3021142).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CLNK	NM_052964.4	c.1107G>C	p.Gln369His	missense_variant	18/19	ENST00000226951.11	NP_443196.2
CLNK	XM_011513775.3	c.1152G>C	p.Gln384His	missense_variant	18/19		XP_011512077.1
CLNK	XM_017007684.2	c.1152G>C	p.Gln384His	missense_variant	18/19		XP_016863173.1
LOC105374482	XR_925387.4	n.261+4734C>G		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CLNK	ENST00000226951.11	c.1107G>C	p.Gln369His	missense_variant	18/19	1	NM_052964.4	ENSP00000226951.6
CLNK	ENST00000515667.5	c.321G>C	p.Gln107His	missense_variant	4/5	3		ENSP00000427256.1
ENSG00000287154	ENST00000663264.1	n.97-28845C>G		intron_variant

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.89e-7 AC: 1 AN: 1450558 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 721440

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000241

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.: 33

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 20, 2024

The c.1107G>C (p.Q369H) alteration is located in exon 18 (coding exon 17) of the CLNK gene. This alteration results from a G to C substitution at nucleotide position 1107, causing the glutamine (Q) at amino acid position 369 to be replaced by a histidine (H). 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	Uncertain	0.52
BayesDel_addAF	Benign	-0.014	T
BayesDel_noAF	Benign	-0.26
CADD	Uncertain	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.38	T;.;T
Eigen	Uncertain	0.50
Eigen_PC	Uncertain	0.51
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.67	T;T;T
M_CAP	Benign	0.018	T
MetaRNN	Benign	0.30	T;T;T
MetaSVM	Benign	-0.66	T
MutationAssessor	Benign	1.8	L;.;.
PrimateAI	Benign	0.41	T
PROVEAN	Benign	-2.4	N;D;.
REVEL	Benign	0.29
Sift	Benign	0.043	D;T;.
Sift4G	Uncertain	0.0070	D;D;D
Polyphen		1.0	D;.;.
Vest4		0.43
MutPred		0.53		Gain of sheet (P = 0.0827);.;Gain of sheet (P = 0.0827);
MVP		0.24
MPC		0.034
ClinPred		0.89	D
GERP RS		5.4
Varity_R		0.15
gMVP		0.46

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs1717035780; hg19: chr4-10502913;